Platelet adenosine diphosphate receptor antagonists

ABSTRACT

Compounds of the following formula: 
                         
where m, n, R 1 , R 2 , R 3 , R 4  and R 6  are described herein, are useful as inhibitors of platelet adenosine diphosphate. Pharmaceutical compositions containing these compounds, methods of using these compounds as antithrombotic agents and processes for synthesizing these compounds are also described herein.

This application claims priority to U.S. Provisional Application Ser.No. 60/432,792 filed Dec. 11, 2002 the entirety of which is incorporatedherein by reference.

FIELD OF THE INVENTION

The invention relates to quinoline derivatives, their use as plateletadenosine diphosphate receptor antagonists, compositions containing themand processes for their preparation.

BACKGROUND OF THE INVENTION

Platelets interact with the coagulation and fibrinolysis systems in themaintenance of hemostasis and in the pathogenesis of thrombosis andthromboembolism. Platelets rapidly adhere to damaged vascular tissue,and release a variety of prothrombotic, chemotactic, and mitogenicfactors, aimed at prompting hemostasis and wound healing. Platelets alsoplay an important role in arterial thrombosis, a common cause of deathand disability in patients with cardiovascular disease. Plateletinhibitors have been successfully used for secondary prevention ofarterial thrombosis in patients with coronary, cerebral, and peripheralvascular disease.

Platelets adhere to exposed subendothelium after vessel wall injury bybinding to von Willebrand factor (vWf) and collagen. This inducesplatelets to change shape from a disc shape to a round form withpseudopodia, which enforces platelet adhesion and aggregation. The finalcommon pathway for platelet aggregation is the activation of thefibrinogen receptor (GPIIb-IIIa). As a result, dimeric fibrinogenmolecules present in plasma can bind and link platelets together to formaggregates.

Activated platelets secrete their granule contents, many of which actdirectly on blood cells, including platelets themselves, andendothelium. Platelets contain several kinds of secretory granules. Thedense-granules contain adenosine diphosphate (“ADP”), adenosinetriphosphate (“ATP”) and serotonin. The α-granules contain severalplatelet-specific proteins (platelet factor 4 and β-thromboglobulin),growth factors (PDGF, TGF-β, EGF and ECGF) and coagulation factors(fibrinogen, Factor V and vWf). Platelets also secrete biologicallyactive arachidonic acid products. Well known is TxA₂ which is inhibitedby aspirin through irreversible inactivation of the cyclooxygenaseproducing TxA₂.

Many stimuli, such as thrombin, collagen, ADP and thromboxane A2 (TxA₂),activate platelets by binding to their cell surface receptors. Most ofthese receptors are G-protein-coupled receptors. Activation ofG-proteins has been shown to be an essential event in plateletactivation. For example, platelets from Gq−/− mice do not aggregate inresponse to thrombin, collagen, ADP or TxA₂ (Offermans, S. et al.,Nature (1998), Vol. 389, No. 11, pp. 183–185). Many down-streamsignaling events have been elucidated, including activation ofphospholipase-C (PLC) and protein kinase C, increase in intracellularcalcium concentration, decrease in cAMP level and tyrosinephosphorylation.

ADP plays a pivotal role in platelet activation. ADP not only causesprimary aggregation of platelets but is also responsible for thesecondary aggregation following activation by other agonists such asthrombin and collagen. Contained at very high concentrations in theplatelet dense-granules, ADP is released when platelets are activated toreinforce platelet aggregation.

ADP-induced platelet activation plays an important role in maintainingnormal hemostasis. Several congenital bleeding disorders have beenlinked to the decreased number of platelet ADP receptors and deficiencyof ADP-induced platelet aggregation. Patients having “storage pooldisease”, which is due to defects in the storage of nucleotides and/ortheir secretion from the platelet dense-granules, have impaired plateletaggregation in response to collagen and other stimuli due to the absenceof the amplification effects by ADP.

ADP-induced platelet activation also plays a key role in the initiationand propagation of thrombosis. Administration of ADP has been shown toinduce thrombus formation in rat and mice mesenteric venules. Incontrast, ADP-removing enzymes have been shown to dramatically reduceplatelet deposition on collagen and to inhibit laser-induced thrombosisin rat mesenteric arterioles and venules, supporting the theory that ADPplays a role in mediating platelet recruitment in thrombus formation.Several ADP-induced early signaling events in platelets have beendescribed. These include a transient rise in free cytoplasmic calcium,an inhibition of adenylate cyclase through activation of G_(i2), anincrease in cytosolic pH by activating the Na+/H+-exchange, and exposureof the platelet binding sites for fibrinogen independent of proteinkinase C. While these signaling events collectively contribute toplatelet aggregation, the specific role of each remains the subject ofon-going investigations.

The current model of ADP-induced platelet activation involves twoG-protein coupled purinergic receptors, one of which is coupled to theactivation of the phospholipase-C pathway (P2Y₁) and the other iscoupled to the inhibition of adenylate cyclase (P2Y_(AC)). P2Y_(AC) isthe best target for a platelet ADP receptor antagonist for severalreasons. First, P2Y_(AC) is predominately platelet specific. Secondly,it is required for ADP-induced aggregation. Thirdly, it plays animportant role in sustaining thrombin or collagen-induced aggregation.Finally, it is the molecular target for anti-aggregatory drugs such asClopidogrel and Ticlopidine. Both of these drugs have been shown to beefficacious in various thrombosis models. However, Clopidogrel has beenshown to be an irreversible inhibitor of platelet aggregation with aslow onset of action. Similarly, the ATP analogues, AR-C67085 andAR-C69931MX, which are potent antagonists for ADP-induced plateletaggregation, have also been shown to be effective in thrombosis modelsand are currently under clinical investigation. All these findingsindicate that ADP is a critical mediator of arterial thrombus formationand hence an excellent target for antithrombotic intervention.

When the properties of current oral platelet inhibitors, such asaspirin, Clopidogrel and Ticlopidine are compared, it becomes clearthat, while relatively safe, current oral platelet inhibitors are onlymodestly effective in preventing thrombotic complications in patientswith underlying vascular disease. It is clear that there is a need inthis field for a potent, selective, reversible, orally active plateletADP receptor (P2Y_(AC)) inhibitor.

SUMMARY OF THE INVENTION

The compounds of the invention are antagonists of the platelet ADPreceptor, P2Y_(AC), and are therefore useful in treating disease-statescharacterized by thrombotic activity and in so doing are useful asantithrombotic agents in the treatment and prevention of thrombosis.Accordingly, in one aspect, the invention is directed to compoundsselected from the group consisting of the following formula (I):

wherein:

-   m and n are independently 1 to 4;-   R¹ is hydrogen, alkyl, carboxyalkyl, aryl, aralkyl, alkylcarbonyl,    aryloxyalkylcarbonyl, carboxyalkylcarbonyl,    alkoxycarbonylalkylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonyl,    arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl, cycloalkylcarbonyl,    haloalkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl,    dialkylaminocarbonyl, alkoxycarbonylaminocarbonyl, or    heterocyclylcarbonyl;-   R² is hydrogen, alkyl, aryl, aralkyl, alkylsulfonylalkyl,    aralkoxyalkyl, hydroxyalkyl, aminoalkyl,    haloalkylsulfonylaminoalkyl, carboxyalkylthioalkyl,    alkoxycarbonylalkylthioalkyl, carboxyalkyl, (carboxy)(hydroxy)alkyl,    carboxyalkoxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl,    carboxyalkoxycarbonylalkyl, alkoxycarbonylalkoxycarbonylalkyl,    aminocarbonylalkyl, aralkoxycarbonylaminoalkyl,    alkoxycarbonylalkylaminocarbonylalkyl,    carboxyalkylaminocarbonylalkyl,    (alkoxycarbonylalkyl)(alkyl)aminocarbonylalkyl,    (carboxyalkyl)(alkyl)aminocarbonylalkyl, or heterocyclylalkyl;-   R³ is aryl or aryloxy each independently optionally substituted by    one or more substituents selected from the group consisting of    alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, —R⁸—OR⁷,    —R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷, —R⁸—N(R⁷)₂,    —R⁸—N(R⁷)C(O)R⁷, —R⁸—N(R⁷)C(O)OR⁹, —R⁸—N(R⁷)—S(O)₂—R⁷, and    —R⁸—C[N(R⁷)₂]—C(O)OR⁷;-   or R³ is aralkyl or aralkoxy, wherein the alkyl radical in the    aralkyl or aralkoxy substituent is optionally substituted by one or    more substituents selected from the group consisting of halo, cyano,    nitro, —R⁸—OR⁷, —R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷, —R⁸—N(R⁷)₂,    —R⁸—N(R⁷)C(O)R⁷, and —R⁹—N(R⁷)C(O)OR⁹), and wherein the aryl radical    in the aralkyl or aralkoxy substituent is independently optionally    substituted by one or more substituents selected from the group    consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl,    —R⁸—OR⁷, —R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷, —R⁸—N(R⁷)₂,    —R⁸—N(R⁷)C(O)R⁷, —R⁸—N(R⁷)C(O)OR⁹, —R⁸—N(R⁷)—S(O)₂—R⁷, and    —R⁸—C[N(R⁷)₂]—C(O)OR⁷;-   each R⁴ is independently selected from the group consisting of    hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy,    hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl,    alkylcarbonyl, nitro, amino, monoalkylamino, dialkylamino,    carboxyalkylamino, alkylcarbonylamino, di(alkylcarbonyl)amino,    hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy,    alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclylalkoxy;-   each R⁵ is independently selected from the group consisting of    hydrogen, alkyl, hydroxyalkyl, aralkyl, carboxy, alkoxycarbonyl,    aralkoxycarbonyl, carboxyalkyl, and alkoxycarbonylalkyl;-   R⁶ is hydrogen, alkyl, carboxyalkyl, or alkoxycarbonylalkyl;-   each R⁷ is hydrogen, alkyl, aryl, aralkyl, or haloalkyl;-   each R⁸ is a bond or a straight or branched alkylene chain; and-   each R⁹ is hydrogen, alkyl, aralkyl or haloalkyl;-   as a single stereoisomer, a mixture of individual stereoisomers, or    a racemic mixture;-   or a pharmaceutically acceptable salt thereof.

In another aspect, this invention is compounds selected from the groupconsisting of the following formula (II):

wherein:

-   m and n are independently 1 to 4;-   R¹ is hydrogen, alkyl, carboxyalkyl, aryl, aralkyl, alkylcarbonyl,    aryloxyalkylcarbonyl, carboxyalkylcarbonyl,    alkoxycarbonylalkylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonyl,    arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl, cycloalkylcarbonyl,    haloalkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl,    dialkylaminocarbonyl, alkoxycarbonylaminocarbonyl, or    heterocyclylcarbonyl;-   R² is hydrogen, alkyl, aryl, aralkyl, alkylsulfonylalkyl,    aralkoxyalkyl, hydroxyalkyl, aminoalkyl,    haloalkylsulfonylaminoalkyl, carboxyalkylthioalkyl,    alkoxycarbonylalkylthioalkyl, carboxyalkyl, (carboxy)(hydroxy)alkyl,    carboxyalkoxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl,    carboxyalkoxycarbonylalkyl, alkoxycarbonylalkoxycarbonylalkyl,    aminocarbonylalkyl, aralkoxycarbonylaminoalkyl,    alkoxycarbonylalkylaminocarbonylalkyl,    carboxyalkylaminocarbonylalkyl,    (alkoxycarbonylalkyl)(alkyl)aminocarbonylalkyl,    (carboxyalkyl)(alkyl)aminocarbonylalkyl, or heterocyclylalkyl;-   R³ is heteroaryl optionally substituted by one or more substituents    selected from the group consisting of alkyl, halo, haloalkyl, cyano,    nitro, tetrazolyl, —R⁸—OR⁷, —R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷,    —R⁸—N(R⁷)₂, —R⁸—N(R⁷)C(O)R⁷, —R⁸—N(R⁷)C(O)OR⁹, —R⁸—N(R⁷)—S(O)₂—R⁷,    and —R⁸—C[N(R⁷)₂]—C(O)OR⁷;-   or R³ is heteroarylalkoxy, wherein the alkoxy radical in the    heteroarylalkoxy substituent is optionally substituted by one or    more substituents selected from the group consisting of halo, cyano,    nitro, —R⁸—OR⁷, —R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷, —R⁸—N(R⁷)₂,    —R⁸—N(R⁷)C(O)R⁷, and —R⁹—N(R⁷)C(O)OR⁹), and wherein the heteroaryl    radical in the heteroarylalkoxy substituent is independently    optionally substituted by one or more substituents selected from the    group consisting of alkyl, halo, haloalkyl, cyano, nitro,    tetrazolyl, —R⁸—OR⁷, —R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷,    —R⁸—N(R⁷)₂, —R⁸—N(R⁷)C(O)R⁷, —R⁸—N(R⁷)C(O)OR⁹, —R⁸—N(R⁷)—S(O)₂—R⁷,    and —R⁸—C[N(R⁷)₂]—C(O)OR⁷;-   each R⁴ is independently selected from the group consisting of    hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy,    hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl,    alkylcarbonyl, nitro, amino, monoalkylamino, dialkylamino,    carboxyalkylamino, alkylcarbonylamino, di(alkylcarbonyl)amino,    hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy,    alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclylalkoxy;-   each R⁵ is independently selected from the group consisting of    hydrogen, alkyl, hydroxyalkyl, aralkyl, carboxy, alkoxycarbonyl,    aralkoxycarbonyl, carboxyalkyl, and alkoxycarbonylalkyl;-   R⁶ is hydrogen, alkyl, carboxyalkyl, or alkoxycarbonylalkyl;-   each R⁷ is hydrogen, alkyl, aryl, aralkyl, or haloalkyl;-   each R⁸ is a bond or a straight or branched alkylene chain; and-   each R⁹ is hydrogen, alkyl, aralkyl or haloalkyl;-   as a single stereoisomer, a mixture of individual stereoisomers, or    a racemic mixture;-   or a pharmaceutically acceptable salt thereof.

In another aspect, this invention is directed to pharmaceuticalcompositions useful in treating a mammal having a disease-statecharacterized by thrombotic activity, which composition comprises apharmaceutically acceptable excipient and a compound of formula (I) or acompound of formula (II) as defined above.

In another aspect, this invention is directed to methods of treatingdisease-states characterized by thrombotic activity, which methodscomprise administering to a mammal having a disease-state characterizedby thrombotic activity a therapeutically effective amount of a compoundof formula (I) or formula (II) as defined above.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated:

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to eight carbon atoms, and which isattached to the rest of the molecule by a single bond, e.g., methyl,ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), and the like. Unless stated otherwisespecifically in the specification, it is understood that for radicals,as defined below, that contain a substituted alkyl group that thesubstitution can occur on any carbon of the alkyl group.

“Alkylene chain” refers to a straight or branched divalent hydrocarbonchain consisting solely of carbon and hydrogen, containing nounsaturation and having from one to eight carbon atoms, e.g., methylene,ethylene, propylene, n-butylene, and the like.

“Alkylcarbonyl” refers to a radical of the formula —C(O)—R_(a) whereR_(a) is an alkyl radical as defined above, e.g., acetyl, ethylcarbonyl,n-propylcarbonyl, and the like.

“Alkylcarbonylamino” refers to a radical of the formula —N(H)—C(O)—R_(a)where R_(a) is an alkyl radical as defined above, e.g., acetylamino,ethylcarbonylamino, n-propylcarbonylamino, and the like.

“Alkylthio” refers to a radical of the formula —S—R_(a) where R_(a) isan alkyl radical as defined above, e.g., methylthio, ethylthio,n-propylthio, and the like.

“Alkylsulfonylalkyl” refers to a radical of the formula—R_(a)—S(O)₂—R_(a) where each R_(a) is independently an alkyl radical asdefined above, e.g., methylsulfonylmethyl, 2-methylsulfonylethyl,2-ethylsulfonylpropyl, and the like.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl radical as defined above, e.g., methoxy, ethoxy, n-propoxy,1-methylethoxy (iso-propoxy), n-butoxy, n-pentoxy, 1,1-dimethylethoxy(t-butoxy), and the like.

“Alkoxycarbonyl” refers to a radical of the formula —C(O)OR_(a) whereR_(a) is an alkyl radical as defined above, e.g., methoxycarbonyl,ethoxycarbonyl, n-propoxycarbonyl, and the like.

“Alkoxycarbonylalkyl” refers to a radical of the formula—R_(a)—C(O)OR_(a) where each R_(a) is independently an alkyl radical asdefined above, e.g., methoxycarbonylmethyl,(1,1-dimethylethoxy)carbonylmethyl, 2-(methoxycarbonyl)ethyl, and thelike.

“Alkoxycarbonylaminocarbonyl” refers to a radical of the formula—C(O)—N(H)—C(O)OR_(a) where R_(a) is an alkyl radical as defined above,e.g., methoxycarbonylaminocarbonyl, ethoxycarbonylaminocarbonyl,n-propoxycarbonylaminocarbonyl, and the like.

“Alkoxyalkoxyalkylcarbonyl” refers to a radical of the formula—C(O)—R_(a)—O—R_(a)—O—R_(a) where each R_(a) is independently an alkylradical as defined above, e.g., 2-(ethoxy)ethoxymethylcarbonyl,3-(2-(n-butoxy)ethoxy)propylcarbonyl, and the like.

“Alkoxycarbonylalkyl” refers to a radical of the formula—R_(a)—C(O)OR_(a) where each R_(a) is independently an alkyl radical asdefined above, e.g., methoxycarbonylmethyl, 2-(ethoxycarbonyl)ethyl,2-(methoxycarbonyl)propyl, and the like.

“Alkoxycarbonylalkoxy” refers to a radical of the formula—O—R_(a)—C(O)OR_(a) where each R_(a) is independently an alkyl radicalas defined above, e.g., methoxycarbonylmethoxy,2-(ethoxycarbonyl)ethoxy, 2-(methoxycarbonyl)propoxy, and the like.

“Alkoxycarbonylalkylcarbonyl” refers to a radical of the formula—C(O)—R_(a)—C(O)OR_(a) where each R_(a) is independently an alkylradical as defined above, e.g., methoxycarbonylmethylcarbonyl,2-(ethoxycarbonyl)ethylcarbonyl, 2-(methoxycarbonyl)propylcarbonyl, andthe like.

“Alkoxycarbonylalkylaminocarbonylalkyl” refers to a radical of theformula —R_(a)—C(O)—N(H)—R_(a)—C(O)OR_(a) where each R_(a) isindependently an alkyl radical as defined above, e.g.,methoxycarbonylmethyl, 2-(ethoxycarbonyl)ethylaminocarbonylmethyl,2-(2-(methoxycarbonyl)propylaminocarbonyl)propyl, and the like.

“Alkoxycarbonylalkylthioalkyl” refers to a radical of the formula—R_(a)—S—R_(a)—C(O)OR_(a) where each R_(a) is independently an alkylradical as defined above, e.g., methoxycarbonylmethylthiomethyl,2-(ethoxycarbonyl)ethylthiomethyl,2-(2-(methoxycarbonyl)propylthio)propyl, and the like.

“Alkoxycarbonylalkoxycarbonylalkyl” refers to a radical of the formula—R_(a)—C(O)—O—R_(a)—C(O)OR_(a) where each R_(a) is independently analkyl radical as defined above, e.g., methoxycarbonylmethoxy,2-(ethoxycarbonyl)ethoxycarbonylmethyl,3-(2-(methoxycarbonyl)propoxycarbonyl)propyl, and the like.

“(Alkoxycarbonylalkyl)(alkyl)aminocarbonylalkyl” refers to a radical ofthe formula —R_(a)—C(O)—N(R_(a))—R_(a)—C(O)OR_(a) where each R_(a) isindependently an alkyl radical as defined above, e.g.,(methoxycarbonylmethyl)(methyl)aminocarbonylmethyl,2-((ethoxycarbonylmethyl)(methyl)aminocarbonyl)ethyl, and the like.

“Amino” refers to the —NH₂ radical.

“Aminoalkyl” refers to a radical of the formula —R_(a)—NH₂, e.g.,aminomethyl, 2-aminomethyl, 2-aminopropyl, and the like.

“Aminocarbonyl” refers to the —C(O)NH₂ radical.

“Aminocarbonylalkoxy” refers to a radical of the formula—O—R_(a)—C(O)NH₂, e.g., aminocarbonylmethoxy, 2-(aminocarbonyl)ethoxy,2-(aminocarbonyl)propoxy, and the like.

“Aminocarbonylalkyl” refers to a radical of the formula —R_(a)—C(O)NH₂,e.g., aminocarbonylmethyl, 2-(aminocarbonyl)ethyl,2-(aminocarbonyl)propyl, and the like.

“Aryl” refers to a phenyl or naphthyl radical. Unless stated otherwisespecifically in the specification, the term “aryl” or the prefix “ar-”(such as in “aralkyl”) is meant to include aryl radicals optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, —R⁸—OR⁷,—R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷, —R⁸—N(R⁷)₂, —R⁸—N(R⁷)C(O)R⁷,—R⁸—N(R⁷)C(O)OR⁹, —R⁸—N(R⁷)—S(O)₂—R⁷, —R⁸—C[N(R⁷)₂]—C(O)OR⁷, whereineach R⁷ is hydrogen, alkyl, aryl, aralkyl, or haloalkyl, each R⁸ is abond or a straight or branched alkylene chain, and each R⁹ is hydrogen,alkyl, aralkyl or haloalkyl as defined herein.

“Aralkyl” refers to a radical of the formula —R_(a)R_(b) where R_(a) isan alkyl radical as defined above, substituted by R_(b), an arylradical, as defined above, e.g., benzyl. The R_(a) radical may beoptionally substituted by one or more substituents selected from thegroup consisting of halo, cyano, nitro, —R⁸—OR⁷, —R⁸—C(O)OR⁷,—R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷, —R⁸—N(R⁷)₂, —R⁸—N(R⁷)C(O)R⁷, and—R⁹—N(R⁷)C(O)OR⁹, wherein each R⁷ is hydrogen, alkyl, aryl, aralkyl, orhaloalkyl, each R⁸ is a bond or a straight or branched alkylene chain,and each R⁹ is hydrogen, alkyl, aralkyl or haloalkyl as defined herein.The R_(b) radical may be optionally substituted one or more substituentsselected from the group consisting of alkyl, halo, haloalkyl, cyano,nitro, tetrazolyl, —R⁸—OR⁷, —R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷,—R⁸—N(R⁷)₂, —R⁸—N(R⁷)C(O)R⁷, —R⁸—N(R⁷)C(O)OR⁹, —R⁸—N(R⁷)—S(O)₂—R⁷,—R⁸—C[N(R⁷)₂]—C(O)OR⁷, wherein each R⁷ is hydrogen, alkyl, aryl,aralkyl, or haloalkyl, each R⁸ is a bond or a straight or branchedalkylene chain, and each R⁹ is hydrogen, alkyl, aralkyl or haloalkyl asdefined herein.

“Aryloxy” refers to a radical of the formula —OR_(b) where R_(b) is anoptionally substituted aryl radical as defined above, e.g., phenoxy.

“Arylcarbonyl” refers to a radical of the formula —C(O)—R_(b) whereR_(b) is an optionally substituted aryl radical as defined above, e.g.,phenylcarbonyl, (4-acetylaminophenyl)carbonyl,(2-methoxyphenyl)carbonyl, and the like. For R¹, preferred arylcarbonylradicals are those radicals wherein the R_(b) group is optionallysubstituted by by one or more substituents independently selected fromthe group consisting of acetylamino, carboxy, aminocarbonyl,alkoxycarbonyl, haloalkoxy, alkoxy, and alkyl.

“Aryloxycarbonyl” refers to a radical of the formula —C(O)OR_(b) whereR_(b) is an optionally substituted aryl radical as defined above, e.g.,phenoxycarbonyl.

“Aryloxyalkylcarbonyl” refers to a radical of the formula—C(O)OR_(b)R_(a) where R_(a) is an alkyl radical, as defined above,substituted by R_(b), an optionally substituted aryl radical, as definedabove, e.g., phenoxymethylcarbonyl, (2-phenoxyethyl)carbonyl, and thelike.

“Aralkoxy” refers to a radical of the formula —OR_(e) where R_(e) is anoptionally substituted aralkyl radical as defined above, e.g.,benzyloxy, 3-phenylpropoxy, and the like.

“Aralkoxyalkyl” refers to a radical of the formula —R_(a)—OR_(e) whereR_(a) is an alkyl radical as defined above and R_(e) is an optionallysubstituted aralkyl radical as defined above, e.g., benzyloxymethyl,2-(benzyloxy)ethyl, 2-(benzyloxy)propyl, and the like.

“Aralkoxycarbonyl” refers to a radical of the formula —C(O)OR_(e) whereR_(e) is an optionally substituted aralkyl radical as defined above,e.g., benzyloxycarbonyl, and the like.

“Aralkoxycarbonylalkyl” refers to a radical of the formula—R_(a)—C(O)OR_(e) where R_(a) is an alkyl radical as defined above andR_(e) is an optionally substituted aralkyl radical as defined above,e.g., benzyloxycarbonylmethyl, 2-(benzyloxycarbonyl)ethyl,3-((naphthalen-2-yl)oxy)carbonyl)propyl, and the like.

“Aralkoxycarbonylaminoalkyl” refers to a radical of the formula—R_(a)—N(H)—C(O)OR_(e) where R_(a) is an alkyl radical as defined aboveand R_(e) is an optionally substituted aralkyl radical as defined above,e.g., benzyloxycarbonylaminomethyl, 2-(benzyloxycarbonylamino)ethyl,2-(benzyloxycarbonylamino)propyl, and the like.

“Carboxy” refers to the —C(O)OH radical.

“Carboxyalkyl” refers to a radical of the formula —R_(a)—C(O)OH, whereR_(a) is an alkyl radical as defined above, e.g., carboxymethyl,2-carboxyethyl, 2-carboxypropyl and the like.

“Carboxyalkoxy” refers to a radical of the formula —O—R_(a)—C(O)OH,where R_(a) is an alkyl radical as defined above, e.g., carboxymethoxy,2-carboxyethoxy, 2-carboxypropoxy, and the like.

“Carboxyalkylcarbonyl” refers to a radical of the formula—C(O)—R_(a)—C(O)OH, where R_(a) is an alkyl radical as defined above,e.g., 2-carboxyethylcarbonyl, carboxymethylcarbonyl,3-carboxypropylcarbonyl, and the like.

“Carboxyalkylamino” refers to a radical of the formula—N(H)—R_(a)—C(O)OH where R_(a) is an alkyl radical as defined above,e.g., carboxymethylamino, 2-carboxyethylamino, 3-carboxypropylamino, andthe like.

“Carboxyalkylaminocarbonylalkyl” refers to a radical of the formula—R_(a)—C(O)—N(H)—R_(a)—C(O)OH where each R_(a) is independently an alkylradical as defined above, e.g., carboxymethylaminocarbonylmethyl,2-(carboxymethylaminocarbonyl)ethyl,2-(2-carboxyethyl)aminocarbonyl)ethyl,3-(2-carboxyethyl)aminocarbonyl)butyl, and the like.

“Carboxyalkylthioalkyl” refers to a radical of the formula—R_(a)—S—R_(a)—C(O)OH were each R_(a) is independently an alkyl radicalas defined above, e.g., carboxymethylthiomethyl,(1-carboxyethyl)thiomethyl, 2-((1-carboxypropyl)thio)ethyl, and thelike.

“Carboxyalkoxyalkyl” refers to a radical of the formula—R_(a)—O—R_(a)—C(O)OH where each R_(a) is independently an alkyl radicalas defined above, e.g., 2-(carboxymethoxy)ethyl,(2-carboxyethoxy)methyl, 3-(2-carboxypropoxy)propyl, and the like.

“Carboxyalkoxycarbonylalkyl” refers to a radical of the formula—R_(a)—C(O)—O—R_(a)—C(O)OH where each R_(a) is independently an alkylradical as defined above, e.g., carboxymethoxycarbonylmethyl,2-(carboxymethoxycarbonyl)ethyl, 2-((2-carboxyethoxy)carbonyl)propyl,and the like.

“Cycloalkyl” refers to a stable 3- to 10-membered monocyclic or bicyclicradical which is saturated, and which consist solely of carbon andhydrogen atoms, e.g., cyclopropyl, cyclobutyl, cyclobutyl, cyclohexyl,decalinyl and the like. Unless otherwise stated specifically in thespecification, the term “cycloalkyl” is meant to include cycloalkylradicals which are optionally substituted one or more substituentsselected from the group consisting of alkyl, halo, haloalkyl, cyano,nitro, tetrazolyl, —R⁸—OR⁷, —R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷,—R⁸—N(R⁷)₂, —R⁸—N(R⁷)C(O)R⁷, —R⁸—N(R⁷)C(O)OR⁹, —R⁸—N(R⁷)—S(O)₂—R⁷,—R⁸—C[N(R⁷)₂]—C(O)OR⁷, wherein each R⁷ is hydrogen, alkyl, aryl,aralkyl, or haloalkyl, each R⁸ is a bond or a straight or branchedalkylene chain, and each R⁹ is hydrogen, alkyl, aralkyl or haloalkyl asdefined herein.

“Cycloalkylcarbonyl” refers to a radical of the formula —C(O)—R_(c)where R_(c) is a cycloalkyl radical as defined above, e.g.,cyclobutylcarbonyl, cyclopropylcarbonyl, and the like. For R¹, apreferred cycloalkylcarbonyl radical is that radical wherein the R_(c)group is optionally substituted by a phenyl group.

“(Carboxy)(hydroxy)alkyl” refers to a radical of the formula—R_(a)(OH)—C(O)OH wherein R_(a) is an alkyl radical defined abovesubstituted by an hydroxy radical and a carboxy radical, as definedherein, e.g., 1-carboxy-3-hydroxypropyl, 2-carboxy-4-hydroxybutyl,1-carboxy-5-hydroxypent-2-yl, and the like.

“(Carboxyalkyl)(alkyl)aminocarbonylalkyl” refers to a radical of theformula —R_(a)—C(O)—N(R_(a))—R_(a)—C(O)OH wherein each R_(a) isindependently an alkyl radical as defined above, and wherein thenitrogen atom is substituted by the R_(a) group and the —R_(a)—C(O)OHgroup, e.g., (carboxyethyl)(ethyl)aminocarbonylmethyl,2-((2-carboxyethyl)(methyl)aminocarbonyl)ethyl, and the like.

“Cyano” refers to the —C≡N radical.

“Dialkylamino” refers to a radical of the formula —N(R_(a))—R_(a) whereeach R_(a) is independently an alkyl radical, e.g., dimethylamino,diethylamino, methylethylamino, and the like.

“Dialkylaminocarbonyl” refers to a radical of the formula—C(O)—N(R_(a))—R_(a) where each R_(a) is independently an alkyl radical,e.g., dimethylaminocarbonyl, diethylaminocarbonyl,methyl(ethyl)aminocarbonyl, and the like.

“Dialkylaminoalkyl” refers to a radical of the formula—R_(a)—N(R_(a))—R_(a) where each R_(a) is independently an alkyl radicalas defined above, e.g., dimethylaminomethyl, 2-(diethylamino)ethyl,3-(methyl(ethyl)amino)propyl, and the like.

“Dialkylaminoalkoxy” refers to a radical of the formula—O—R_(a)—N(R_(a))—R_(a) where each R_(a) is independently an alkylradical as defined above, e.g., dimethylaminomethoxy,2-(diethylamino)ethoxy, 3-(methyl(ethyl)amino)propoxy, and the like.

“Di(alkylcarbonyl)amino” refers to a radical of the formula—N(C(O)—R_(a))—C(O)—R_(a) where each R_(a) is independently an alkylradical as defined above, e.g., di(acetyl)amino, di(ethylcarbonyl)amino,and the like.

“Halo” refers to bromo, chloro, iodo or fluoro.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl,1-bromomethyl-2-bromoethyl, and the like.

“Haloalkylsulfonylaminoalkyl” refers to a radical of the formula—R_(a)—N(H)—S(O)₂R_(f) where R_(a) is an alkyl radical as defined aboveand R_(f) is a haloalkyl radical as defined above, e.g.,2-(trifluoromethoxysulfonylamino)ethyl,3-(trifluoromethoxysulfonylamino)propyl, and the like.

“Haloalkoxy” refers to a radical of the formula —OR_(f) where R_(f) isan haloalkyl radical as defined above, e.g., trifluoromethoxy,difluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy,1-fluoromethyl-2-fluoroethoxy, 3-bromo-2-fluoropropoxy,1-bromomethyl-2-bromoethoxy, and the like.

“Haloalkenyloxy” refers to a radical of the formula —OR_(g) where R_(g)is an haloalkenyl radical as defined above, as defined above, e.g.,1,2-difluoroethenyloxy, 3-bromo-2-fluoroprop-1-enyloxy,1,2-dibromoethenyloxy, and the like.

“Haloalkoxycarbonyl” refers to a radical of the formula —C(O)OR_(f)where R_(f) is an haloalkyl radical as defined above, e.g.,trifluoromethoxycarbonyl, difluoromethoxycarbonyl,trichloromethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl,1-fluoromethyl-2-fluoroethoxycarbonyl, 3-bromo-2-fluoropropoxycarbonyl,1-bromomethyl-2-bromoethoxycarbonyl, and the like.

“Hydroxy” refers to the —OH radical.

“Hydroxyalkyl” refers to a alkyl radical as defined above that issubstituted by a hydroxy radical, e.g., hydroxymethyl, 2-hydroxyethyl,2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, andthe like.

“Heterocyclyl” refers to a stable 3- to 15-membered ring radical whichconsists of carbon atoms and from one to five heteroatoms selected fromthe group consisting of nitrogen, oxygen and sulfur. For purposes ofthis invention, the heterocyclyl radical may be a monocyclic, bicyclicor tricyclic ring system, which may include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heterocyclylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized; and the heterocyclyl radical may be aromatic or partiallyor fully saturated. The heterocyclyl radical may be attached to the mainstructure at any heteroatom or carbon atom which results in the creationof a stable compound. Examples of such heterocyclyl radicals include,but are not limited to, azepinyl, acridinyl, benzimidazolyl,benzthiazolyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl,benzofuranonyl, benzothienyl, carbazolyl, cinnolinyl,decahydroisoquinolyl, dioxolanyl, furanyl, furanonyl, isothiazolyl,imidazolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, indolyl,isoindolyl, indolinyl, isoindolinyl, indanyl, indolizinyl, isoxazolyl,isoxazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, oxazolyl,oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, pyridinyl,pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl,quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiazolidinyl,thiadiazolyl, triazolyl, tetrazolyl, tetrahydrofuryl, triazinyl,tetrahydropyranyl, thienyl, thiamorpholinyl, thiamorpholinyl sulfoxide,and thiamorpholinyl sulfone. Unless stated otherwise specifically in thespecification, the term “heterocyclyl” is meant to include heterocyclylradicals as defined above which are optionally substituted one or moresubstituents selected from the group consisting of alkyl, halo,haloalkyl, cyano, nitro, tetrazolyl, —R⁸—OR⁷, —R⁸—C(O)OR⁷,—R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷, —R⁸—N(R⁷)₂, —R⁸—N(R⁷)C(O)R⁷,—R⁸—N(R⁷)C(O)OR⁹, —R⁸—N(R⁷)—S(O)₂—R⁷, —R⁸—C[N(R⁷)₂]—C(O)OR⁷, whereineach R⁷ is hydrogen, alkyl, aryl, aralkyl, or haloalkyl, each R⁸ is abond or a straight or branched alkylene chain, and each R⁹ is hydrogen,alkyl, aralkyl or haloalkyl as defined herein.

“Heteroaryl” refers to a heterocyclyl radical as defined above whereinthe heterocyclyl radical is partially or fully aromatic.

“Heterocyclylalkyl” refers to a radical of the formula —R_(a)—R_(h)where R_(a) is an alkyl radical as defined above and R_(h) is anheterocyclyl radical as defined above, e.g., imidazol-3-ylmethyl,triazol-3-ylmethyl, 2-tetrazolylethyl, and the like. For R², preferredheterocyclylalkylradicals are those radicals where R_(h) is selectedfrom the group consisting of imidazolyl (optionally substituted bycarboxyalkyl), indolyl, triazolyl and tetrazolyl.

“Heterocyclylalkoxy” refers to a radical of the formula —O—R_(a)—R_(h)where R_(a) is an alkyl radical as defined above and R_(h) is anheterocyclyl radical as defined above, e.g., 1-tetrazolylethoxy,oxiranylmethoxy, and the like. For R³, preferred heterocyclylalkoxyradicals are those radicals where R_(h) is selected from the groupconsisting of oxiranyl or tetrazolyl. For R⁴, preferredheterocyclylalkoxy radicals are those radicals where R_(h) ispyrrolidinyl (optionally substituted by one or more substituentsindependently selected from the group consisting of hydroxy andcarboxy).

“Heteroarylalkoxy” refers to a heterocyclylalkoxy radical as definedabove wherein the heterocyclyl radical is partially or fully aromatic.

“Heterocyclylcarbonyl” refers to a radical of the formula —C(O)—R_(h)where R_(h) is a heterocyclyl radical as defined above, e.g.,furan-2-ylcarbonyl, piperidin-4-ylcarbonyl, thien-2-ylcarbonyl,morpholin-4-ylcarbonyl, and the like. For R¹, preferredheterocyclylcarbonyl radicals are those radicals wherein R_(h) isselected from the group consisting of furanyl, thienyl, piperidinyl,morpholinyl and pyridinyl (optionally substituted by one or moresubstitutents independently selected from the group consisting ofhydroxy, halo and alkyl).

“Monoalkylamino” refers to a radical of the formula —N(H)—R_(a) whereR_(a) is an alkyl radical as defined above, e.g., methylamino,ethylamino, n-propylamino, and the like.

“Monoalkylaminocarbonyl” refers to a radical of the formula—C(O)—N(H)—R_(a) where R_(a) is an alkyl radical as defined above, e.g.,methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, and thelike.

“Mammal” includes humans and domesticated animals, such as cats, dogs,swine, cattle, sheep, goats, horses, rabbits, and the like.

“Nitro” refers to the —NO₂ radical.

As used herein, “methods known to one of ordinary skill in the art” maybe identified though various reference books and databases. Suitablereference books and treatise that detail the synthesis of reactantsuseful in the preparation of compounds of the present invention, orprovide references to articles that describe the preparation, includefor example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., NewYork; S. R. Sandler et al., “Organic Functional Group Preparations,” 2ndEd., Academic Press, New York, 1983; H. O. House, “Modern SyntheticReactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L.Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, NewYork, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanismsand Structure”, 4th Ed., Wiley-lnterscience, New York, 1992. Specificand analogous reactants may also be identified through the indices ofknown chemicals prepared by the Chemical Abstract Service of theAmerican Chemical Society, which are available in most public anduniversity libraries, as well as through on-line databases (the AmericanChemical Society, Washington, D.C. may be contacted for more details).Chemicals that are known but not commercially available in catalogs maybe prepared by custom chemical synthesis houses, where many of thestandard chemical supply houses (e.g., those listed above) providecustom synthesis services.

“Prodrugs” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound of the invention. Thus, the term “prodrug” refers to ametabolic precursor of a compound of the invention that ispharmaceutically acceptable. A prodrug may be inactive when administeredto a subject in need thereof, but is converted in vivo to an activecompound of the invention. Prodrugs are typically rapidly transformed invivo to yield the parent compound of the invention, for example, byhydrolysis in blood. The prodrug compound often offers advantages ofsolubility, tissue compatibility or delayed release in a mammalianorganism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7–9, 21–24(Elsevier, Amsterdam).

A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugsas Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated in full by reference herein.

The term “prodrug” is also meant to include any covalently bondedcarriers which release the active compound of the invention in vivo whensuch prodrug is administered to a mammalian subject. Prodrugs of acompound of the invention may be prepared by modifying functional groupspresent in the compound of the invention in such a way that themodifications are cleaved, either in routine manipulation or in vivo, tothe parent compound of the invention. Prodrugs include compounds of theinvention wherein a hydroxy, amino or mercapto group is bonded to anygroup that, when the prodrug of the compound of the invention isadministered to a mammalian subject, cleaves to form a free hydroxy,free amino or free mercapto group, respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol and amine functional groups in the compounds ofthe invention and the like.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid and the like, andorganic acids such as acetic acid, trifluoroacetic acid, propionic acid,glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid,succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly preferredorganic bases are isopropylamine, diethylamine, ethanolamine,trimethylamine, dicyclohexylamine, choline and caffeine.

“Therapeutically effective amount” refers to that amount of a compoundof the invention which, when administered to a human in need thereof, issufficient to effect treatment, as defined below, for a disease-statecharacterized by thrombotic activity. The amount of a compound of theinvention which constitutes a “therapeutically effective amount” willvary depending on the compound, the condition and its severity, and theage of the human to be treated, but can be determined routinely by oneof ordinary skill in the art having regard to his own knowledge and tothis disclosure.

“Treating” or “treatment” as used herein covers the treatment of adisease-state in a mammal, preferably a human, which disease-stated ischaracterized by thrombotic activity, and includes:

(i) preventing the condition from occurring in a human, in particular,when such human is predisposed to the condition but has not yet beendiagnosed as having it;

(ii) inhibiting the condition, i.e., arresting its development; or

(iii) relieving the condition, ie., causing regression of the condition.

In the above definitions, the use of parentheses in a formula is used toconserve space. Accordingly, the use of parenthesis in a formulaindicates that the group enclosed within the parentheses is attacheddirectly to the atom preceding the parenthesis. For example, the term“(carboxy)(hydroxy)alkyl” is defined as a radical of the formula—R_(a)(OH)—C(O)OH. This formula can be drawn as follows:

It will also be appreciated that certain compounds of the invention orpharmaceutically acceptable salts thereof, may exist in, and be isolatedin, isomeric forms, including tautomeric forms, cis- or trans-isomers.In addition, certain compounds of the invention or pharmaceuticallyacceptable salts thereof may contain one or more asymmetric centers andmay thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, such as (R)- or (S)-. The present invention is meant toinclude all such possible isomers, as well as their racemic andoptically pure forms. Optically active (R)- and (S)-isomers may beprepared using chiral synthons or chiral reagents by methods known tothose of ordinary skill in the art, or resolved using conventionaltechniques. When the compounds described herein contain olefinic doublebonds or other centers of geometric asymmetry, and unless specifiedotherwise, it is intended that the compounds include both E and Zgeometric isomers.

The nomenclature used herein is a modified form of the I.U.P.A.C.nomenclature system wherein the compounds of the invention are namedherein as derivatives of the quinoline moiety.

is named herein as2-[1S-(4-(methoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline.Unless otherwise indicated, compound names are intended to include anysingle stereoisomer, enantiomer, racemate or mixtures thereof.Utility of the Compounds of the Invention

The compounds of the invention act as reversible, selective antagonistsof the platelet ADP receptor, P2Y_(AC). Accordingly, the compounds areuseful in treating disease-states which are characterized as havingthrombotic activity. In particular, the compounds are useful asinhibitors of platelet activation, aggregation and degranulation,anti-thrombotic agents or in the treatment or prophylaxis of unstableangina, coronary angioplasty (PTCA), myocardial infarction,perithrombolysis, primary arterial thrombotic I complications ofatherosclerosis such as thrombotic or embolic stroke, peripheralvascular disease, myocardial infarction with or without thrombolysis,arterial complications due to interventions in atherosclerotic diseasesuch as angioplasty, endarterectomy, stent placement, coronary and othervascular graft surgery, thrombotic complications of surgical ormechanical damage such as tissue salvage following accidental orsurgical trauma, reconstructive surgery including skin and muscle flaps,conditions with a diffuse thrombotic/platelet consumption component suchas disseminated intravascular coagulation, thrombotic thrombocytopenicpurpura, hemolytic uremic syndrome, thrombotic complications ofsepticernia, adult respiratory distress syndrome, anti-phospholipidsyndrome, heparin-induced thrombocytopaenia and pre-eclampsia/eclampsia,or venous thrombosis such as deep vein thrombosis, venoocclusivedisease, hematological conditions such as myeloproliferative disease,including thrombocythemia; or in the prevention of mechanically-inducedplatelet activation in vivo, such as cardiopulmonary bypass (preventionof microthromboembolism), mechanically-induced platelet activation invitro, such as use in the preservation of blood products, e.g. plateletconcentrates, or shunt occlusion such as in renal dialysis andplasmapheresis, thrombosis secondary to vascular damage/inflammationsuch as vasculitis, arteritis, glomerulonephritis, inflammatory boweldisease and organ graft rejection, conditions such as migraine,Raynaud's phenomenon, atheromatous plaque formation/progression,vascular stenosis/restenosis and asthma, in which platelet-derivedfactors are implicated in the disease process.

The compounds of formula (I) are also useful as standard or referencecompounds, for example, as a quality standard or control, in tests orassays involving the inhibition of the platelet ADP receptor, P2Y_(AC).Such compounds may be provided in a commercial kit, for example, for usein pharmaceutical research involving the platelet ADP receptor,P2Y_(AC). For example, a compound of formula (I) could be used as areference in an assay to compare its known activity to a compound withan unknown activity. This would ensure that the experimenter that theassay was being performed properly and provide a basis for comparison,especially if the test compound was a derivative of the referencecompound. When developing new assays or protocols, compounds of formula(I) could be used to test their effectiveness.

Testing of the Compounds of the Invention

The ability of the compounds to inhibit the platelet adenosinediphosphate receptor known as the P2Y_(AC) receptor, and its biologicaleffects may be tested in a variety of in vitro, ex vivo and in vivoassays. For example, the ability of the compounds to bind to theP2Y_(AC) receptor may be measured by methods similar to those describedin Gachet, C. et al., Br. J. Haemotol. (1995), Vol. 91, pp. 434–444 andMills, D. C. B., Thromb. Haemost. (1996), Vol. 76, No. 6, pp. 835–856,and by the method described below in Example 4. The ability of thecompounds to inhibit ADP-induced aggregation of platelets may bemeasured by methods similar to those described in R. G. Humphries, Br.J. Pharm. (1995), Vol. 115, pp. 1110–1116 and Methods in Enzymology,Vol. 169, p. 3 and by the method described below in Example 5. Theability of the compounds to inhibit thrombus formation in vivo or exvivo may be measured by methods similar to those described in J. M.Herbert, Cardiovasc. Drug Reviews (1993), Vol. 11, No. 2, pp. 180–198 orJ. D. Folts, Circulation (1976), Vol. 54, No. 3, p. 365, or by themethods described below in Example 6. The results of these assaysclearly demonstrate that the compounds of the invention are functionalantagonists of the platelet adenosine diphosphate receptor and arethereful useful in inhibiting platelet aggregation and thrombusformation.

Administration of the Compounds of the Invention

Administration of the compounds of the invention, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration or agents for serving similar utilities. Thus,administration can be, for example, orally, nasally, parenterally,topically, transdermally, or rectally, in the form of solid, semi-solid,lyophilized powder, or liquid dosage forms, such as for example,tablets, suppositories, pills, soft elastic and hard gelatin capsules,powders, solutions, suspensions, or aerosols, or the like, preferably inunit dosage forms suitable for simple administration of precise dosages.The compositions will include a conventional pharmaceutical carrier orexcipient and a compound of the invention as the/an active agent, and,in addition, may include other medicinal agents, pharmaceutical agents,carriers, adjuvants, etc.

Generally, depending on the intended mode of administration, thepharmaceutically acceptable compositions will contain about 1% to about99% by weight of a compound(s) of the invention, or a pharmaceuticallyacceptable salt thereof, and 99% to 1% by weight of a suitablepharmaceutical excipient. Preferably, the composition will be about 5%to 75% by weight of a compound(s) of the invention, or apharmaceutically acceptable salt thereof, with the rest being suitablepharmaceutical excipients.

The preferred route of administration is oral, using a convenient dailydosage regimen which can be adjusted according to the degree of severityof the disease-state to be treated. For such oral administration, apharmaceutically acceptable composition containing a compound(s) of theinvention, or a pharmaceutically acceptable salt thereof, is formed bythe incorporation of any of the normally employed excipients, such as,for example, pharmaceutical grades of mannitol, lactose, starch,pregelatinized starch, magnesium stearate, sodium saccharine, talcum,cellulose ether derivatives, glucose, gelatin, sucrose, citrate, propylgallate, and the like. Such compositions take the form of solutions,suspensions, tablets, pills, capsules, powders, sustained releaseformulations and the like.

Preferably such compositions will take the form of capsule, caplet ortablet and therefore will also contain a diluent such as lactose,sucrose, dicalcium phosphate, and the like; a disintegrant such ascroscarmellose sodium or derivatives thereof; a lubricant such asmagnesium stearate and the like; and a binder such as a starch, gumacacia, polyvinylpyrrolidone, gelatin, cellulose ether derivatives, andthe like.

The compounds of the invention, or their pharmaceutically acceptablesalts, may also be formulated into a suppository using, for example,about 0.5% to about 50% active ingredient disposed in a carrier thatslowly dissolves within the body, e.g., polyoxyethylene glycols andpolyethylene glycols (PEG), e.g., PEG 1000 (96%) and PEG 4000 (4%).

Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, etc., a compound(s) of the invention(about 0.5% to about 20%), or a pharmaceutically acceptable saltthereof, and optional pharmaceutical adjuvants in a carrier, such as,for example, water, saline, aqueous dextrose, glycerol, ethanol and thelike, to thereby form a solution or suspension.

If desired, a pharmaceutical composition of the invention may alsocontain minor amounts of auxiliary substances such as wetting oremulsifying agents, pH buffering agents, antioxidants, and the like,such as, for example, citric acid, sorbitan monolaurate, triethanolamineoleate, butylated hydroxytoluene, etc.

Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton,Pa., 1990). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease-state characterized by thrombotic activity in accordancewith the teachings of this invention.

The compounds of the invention, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount which willvary depending upon a variety of factors including the activity of thespecific compound employed; the metabolic stability and length of actionof the compound; the age, body weight, general health, sex, and diet ofthe patient; the mode and time of administration; the rate of excretion;the drug combination; the severity of the particular disease-states; andthe host undergoing therapy. Generally, a therapeutically effectivedaily dose is from about 0.14 mg to about 14.3 mg/kg of body weight perday of a compound of the invention, or a pharmaceutically acceptablesalt thereof; preferably, from about 0.7 mg to about 10 mg/kg of bodyweight per day; and most preferably, from about 1.4 mg to about 7.2mg/kg of body weight per day. For example, for administration to a 70 kgperson, the dosage range would be from about 10 mg to about 1.0 gram perday of a compound of the invention, or a pharmaceutically acceptablesalt thereof, preferably from about 50 mg to about 700 mg per day, andmost preferably from about 100 mg to about 500 mg per day.

PREFERRED EMBODIMENTS

Of the compounds of the invention as set forth above in the Summary ofthe Invention, several groups of compounds are particularly preferred.

Of the compounds of formula (I) as set forth above in the Summary of theInvention, a preferred group of compounds is that group of compoundswherein:

-   m is 1;-   n is 1 or 2;-   R¹ is hydrogen, aryl, aralkyl, or alkoxycarbonyl;-   R² is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or    aralkoxycarbonylalkyl;-   R³ is aryl optionally substituted by one or more substituents    selected from the group consisting of alkyl, halo, haloalkyl, cyano,    nitro, —R⁸—OR⁷, —R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷, —R⁸—N(R⁷)₂,    —R⁸—N(R⁷)C(O)R⁷, and —R⁸—N(R⁷)C(O)OR⁹;-   each R⁴ is is independently selected from the group consisting of    hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy,    hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl,    alkylcarbonyl, nitro, amino, monoalkylamino, dialkylamino,    carboxyalkylamino, alkylcarbonylamino, di(alkylcarbonyl)amino,    hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy,    alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclylalkoxy;-   R⁵ is hydrogen;-   R⁶ is hydrogen or alkyl;-   each R⁷ is hydrogen, alkyl, aryl, aralkyl, or haloalkyl;-   each R⁸ is a bond or a straight or branched alkylene chain; and-   R⁹ is hydrogen, alkyl, aralkyl or haloalkyl.

Of this preferred group of compounds, a preferred subgroup of compoundsis that subgroup of compounds wherein:

-   m is 1;-   n is 1 or 2;-   R¹ is hydrogen or alkoxycarbonyl;-   R² is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or    aralkoxycarbonylalkyl;-   R³ is aryl optionally substituted by one or more substituents    selected from the group consisting of carboxy or alkoxycarbonyl;-   each R⁴ is is independently selected from the group consisting of    hydrogen, alkyl, halo, or haloalkyl;-   R⁵ is hydrogen; and-   R⁶ is hydrogen.

Of this preferred subgroup of compounds, a preferred compound is2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-carboxy)phenylquinolinein trifluoroacetic acid.

Another preferred group of compounds of formula (I) is that group ofcompounds wherein:

-   m is 1;-   n is 1 or 2;-   R¹ is hydrogen, aryl, aralkyl, or alkoxycarbonyl;-   R² is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or    aralkoxycarbonylalkyl;-   R³ is aryloxy optionally substituted by one or more substituents    selected from the group consisting of alkyl, halo, haloalkyl, cyano,    nitro, tetrazolyl, —R⁸—OR⁷, —R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷,    —R⁸—N(R⁷)₂, —R⁸N(R⁷)C(O)R⁷, —R⁸—N(R⁷)C(O)OR⁹, —R⁸—N(R⁷)—S(O)₂—R⁷,    and —R⁸—C[N(R⁷)₂]—C(O)OR⁷;-   each R⁴ is independently selected from the group consisting of    hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy,    hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl,    alkylcarbonyl, nitro, amino, monoalkylamino, dialkylamino,    carboxyalkylamino, alkylcarbonylamino, di(alkylcarbonyl)amino,    hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy,    alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclylalkoxy;-   R⁵ is selected from the group consisting of hydrogen, alkyl,    hydroxyalkyl, aralkyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl,    carboxyalkyl, and alkoxycarbonylalkyl;-   R⁶ is hydrogen, alkyl, carboxyalkyl, or alkoxycarbonylalkyl;-   each R⁷is hydrogen, alkyl, aryl, aralkyl, or haloalkyl;-   each R⁸ is a bond or a straight or branched alkylene chain; and-   R⁹ is hydrogen, alkyl, aralkyl or haloalkyl.

Of this preferred group of compounds, a preferred subgroup of compoundsis that subgroup of compounds wherein:

-   m is 1;-   n is 1 or 2;-   R¹ is hydrogen or alkoxycarbonyl;-   R² is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or    aralkoxycarbonylalkyl;-   R³is aryloxy optionally substituted by one or more substituents    selected from the group consisting of alkyl, tetrazolyl,    —R⁸—C(O)OR⁷, —R⁸—N(R⁷)₂, —R⁸—N(R⁷)—S(O)₂—R⁷, and    —R⁸—C[N(R⁷)₂]—C(O)OR⁷;-   each R⁴ is is independently selected from the group consisting of    hydrogen, alkyl, halo, or haloalkyl;-   R⁵ is hydrogen;-   R⁶ is hydrogen;-   each R⁷is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; and-   each R⁸ is a bond or a straight or branched alkylene chain.

Of this preferred subgroup of compounds, preferred compounds areselected from the group consisting of the following:

-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-carboxy)phenoxyquinoline    in 2,2,2-trifluoro-1,1-ethanediol;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(2-carboxy)phenoxyquinoline    in 2,2,2-trifluoro-1,1-ethanediol;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(2-amino-5-carboxy)phenoxyquinoline    in 2,2,2-trifluoro-1,1-ethanediol;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(4-carboxy)phenoxyquinoline    in 2,2,2-trifluoro-1,1-ethanediol;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-carboxymethyl)phenoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-(1-amino-1-carboxy)methyl)phenoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-(2-amino-2-carboxy)ethyl)phenoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(2-methyl-5-carboxy)phenoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(5-carboxy-2-diethylaminomethyl)phenoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-tetrazol-5-yl)phenoxyquinoline    in 2,2,2-trifluoro-1,1-ethanediol;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-trifluoromethylsulfonylamino)phenoxyquinoline    in trifluoroacetic acid; and-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-4-(3-carboxy)phenoxyquinoline    in trifluoroacetic acid.

Another preferred group of compounds of formula (I) is that group ofcompounds wherein:

-   m is 1;-   n is 1 or 2;-   R¹ is hydrogen, aryl, aralkyl, or alkoxycarbonyl;-   R² is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or    aralkoxycarbonylalkyl;-   R³ is aralkyl wherein the alkyl radical in the aralkyl substituent    is optionally substituted by one or more substituents selected from    the group consisting of halo, cyano, nitro, —R⁸—OR⁷, —R⁸—C(O)OR⁷,    —R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷, —R⁸—N(R⁷)₂, —R⁸—N(R⁷)C(O)R⁷, and    —R⁹—N(R⁷)C(O)OR⁹), and wherein the aryl radical in the aralkyl    substituent is independently optionally substituted by one or more    substituents selected from the group consisting of alkyl, halo,    haloalkyl, cyano, nitro, tetrazolyl, —R⁸—OR⁷, —R⁸—C(O)OR⁷,    —R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷, —R⁸—N(R⁷)₂, —R⁸—N(R⁷)C(O)R⁷,    —R⁸—N(R⁷)C(O)OR⁹, —R⁸—N(R⁷)—S(O)₂—R⁷, and —R⁸—C[N(R⁷)₂]—C(O)OR⁷;-   each R⁴ is independently selected from the group consisting of    hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy,    hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl,    alkylcarbonyl, nitro, amino, monoalkylamino, dialkylamino,    carboxyalkylamino, alkylcarbonylamino, di(alkylcarbonyl)amino,    hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy,    alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclylalkoxy;-   R⁵ is selected from the group consisting of hydrogen, alkyl,    hydroxyalkyl, aralkyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl,    carboxyalkyl, and alkoxycarbonylalkyl;-   R⁶ is hydrogen, alkyl, carboxyalkyl, or alkoxycarbonylalkyl;-   each R⁷ is hydrogen, alkyl, aryl, aralkyl, or haloalkyl;-   each R⁸ is a bond or a straight or branched alkylene chain; and-   R⁹ is hydrogen, alkyl, aralkyl or haloalkyl.

Another preferred group of compounds of formula (I) is that group ofcompounds wherein:

-   m is 1;-   n is 1 or 2;-   R¹ is hydrogen, aryl, aralkyl, or alkoxycarbonyl;-   R² is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or    aralkoxycarbonylalkyl;-   R³ is aralkoxy wherein the alkyl radical in the aralkyl substituent    is not optionally substituted and wherein the aryl radical in the    aralkoxy substituent is optionally substituted by one or more    substituents selected from the group consisting of alkyl, halo,    haloalkyl, cyano, nitro, tetrazolyl, —R⁸—OR⁷, —R⁸—C(O)OR⁷,    —R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷, —R⁸—N(R⁷)₂, —R⁸—N(R⁷)C(O)R⁷,    —R⁸—N(R⁷)C(O)OR⁹, —R⁸—N(R⁷)—S(O)₂—R⁷, and —R⁸—C[N(R⁷)₂]—C(O)OR⁷;-   each R⁴ is independently selected from the group consisting of    hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy,    hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl,    alkylcarbonyl, nitro, amino, monoalkylamino, dialkylamino,    carboxyalkylamino, alkylcarbonylamino, di(alkylcarbonyl)amino,    hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy,    alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclylalkoxy;-   R⁵ is selected from the group consisting of hydrogen, alkyl,    hydroxyalkyl, aralkyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl,    carboxyalkyl, and alkoxycarbonylalkyl;-   R⁶ is hydrogen, alkyl, carboxyalkyl, or alkoxycarbonylalkyl;-   each R⁷ is hydrogen, alkyl, aryl, aralkyl, or haloalkyl;-   each R⁸ is a bond or a straight or branched alkylene chain; and-   R⁹ is hydrogen, alkyl, aralkyl or haloalkyl.

Of this preferred group of compounds, a preferred subgroup of compoundsis that subgroup of compounds wherein:

-   m is 1;-   n is 1 or 2;-   R¹ is hydrogen, aryl, aralkyl, or alkoxycarbonyl;-   R² is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or    aralkoxycarbonylalkyl;-   R³ is aralkoxy wherein the aryl radical in the aralkoxy substituent    is optionally substituted by one or more substituents selected from    the group consisting of alkyl, halo, haloalkyl, —R⁸—OR⁷,    —R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂, and —R⁸—N(R⁷)₂;-   each R⁴ is independently selected from the group consisting of    hydrogen, alkyl, alkoxy, halo, or haloalkyl;-   R⁵ is hydrogen;-   R⁶ is hydrogen;-   each R⁷ is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; and-   each R⁸ is a bond or a straight or branched alkylene chain.

Of this preferred subgroup of compounds, preferred compounds areselected from the group consisting of the following:

-   2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-benzyloxyquinoline;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-benzyloxycarbonylpropyl]aminocarbonyl-4-benzyloxyquinoline;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-benzyloxyquinoline;-   2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-benzyloxycarbonylpropyl]aminocarbonyl-4-benzyloxy-8-methoxyquinoline;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-benzyloxy-8-methoxyquinoline;-   2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-(4-methoxycarbonyl)benzyloxyquinoline;-   2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-(4-carboxy)benzyloxyquinoline;-   2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-(3-methoxycarbonyl)benzyloxyquinoline;-   2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-(3-carboxy)benzyloxyquinoline;-   2-[1S-(4-(3-methylphenyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-benzyloxyquinoline;    and-   2-[1S-(4-(3-methylphenyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-benzyloxyquinoline.

Another preferred group of compounds of formula (I) is that group ofcompounds wherein:

-   m is 1;-   n is 1 or 2;-   R¹ is hydrogen, aryl, aralkyl, or alkoxycarbonyl;-   R² is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or    aralkoxycarbonylalkyl;-   R³ is aralkoxy wherein the alkyl radical in the aralkoxy substituent    is substituted by one or more substituents selected from the group    consisting of halo, cyano, nitro, —R⁸—OR⁷, —R⁸—C(O)OR⁷,    —R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷, —R⁸—N(R⁷)₂, —R⁸—N(R⁷)C(O)R⁷, and    —R⁹—N(R⁷)C(O)OR⁹), and wherein the aryl radical in the aralkoxy    substituent is optionally substituted by one or more substituents    selected from the group consisting of alkyl, halo, haloalkyl, cyano,    nitro, tetrazolyl, —R⁸—OR⁷, —R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷,    —R⁸—N(R⁷)₂, —R⁸—N(R⁷)C(O)R⁷, —R⁸—N(R⁷)C(O)OR⁹, —R⁸—N(R⁷)—S(O)₂—R⁷,    and —R⁸—C[N(R⁷)₂]—C(O)OR⁷;-   each R⁴ is independently selected from the group consisting of    hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy,    hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl,    alkylcarbonyl, nitro, amino, monoalkylamino, dialkylamino,    carboxyalkylamino, alkylcarbonylamino, di(alkylcarbonyl)amino,    hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy,    alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclylalkoxy;-   R⁵ is selected from the group consisting of hydrogen, alkyl,    hydroxyalkyl, aralkyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl,    carboxyalkyl, and alkoxycarbonylalkyl;-   R⁶ is hydrogen, alkyl, carboxyalkyl, or alkoxycarbonylalkyl;-   each R⁷ is hydrogen, alkyl, aryl, aralkyl, or haloalkyl;-   each R⁸ is a bond or a straight or branched alkylene chain; and-   R⁹ is hydrogen, alkyl, aralkyl or haloalkyl.

Of this preferred group of compounds, a preferred subgroup of compoundsis that subgroup of compounds wherein:

-   m is 1;-   n is 1 or 2;-   R¹ is hydrogen, aryl, aralkyl, or alkoxycarbonyl;-   R² is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or    aralkoxycarbonylalkyl;-   R³ is aralkoxy wherein the alkyl radical in the aralkoxy substituent    is substituted by —R⁸—C(O)OR⁷, and wherein the aryl radical in the    aralkoxy substituent is optionally substituted by one or more    substituents selected from the group consisting of halo and —R⁸—OR⁷;-   each R⁴ is independently selected from the group consisting of    hydrogen, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or    dialkylamino;-   R⁵ is hydrogen;-   R⁶ is hydrogen;-   each R⁷ is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; and-   each R⁸ is a bond or a straight or branched alkylene chain.

Of this preferred subgroup of compounds, preferred compounds areselected from the group consisting of the following:

-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-(1-phenyl-1-methoxycarbonyl)methoxyquinoline;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(1-phenyl-1-methoxycarbonyl)methoxyquinoline;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(1-phenyl-1-carboxy)methoxyquinoline;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-chloro-4-(1-carboxy-1-phenyl)methoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-naphth-1-yl-1-carboxy)methoxyquinoline;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-chloro-8-fluoro-4-(1-methoxycarbonyl-1-phenyl)methoxyquinoline    in acetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-chloro-8-fluoro-4-(1-carboxy-1-phenyl)methoxyquinoline    in acetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-6-fluoro-4-(1-carboxy-1-(2-fluoro)phenyl)methoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-4-(1-ethoxycarbonyl-1-phenyl)methoxyquinoline    in trifluoroacetic acid;-   2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-6-fluoro-4-(1-carboxy-1-(4-chloro)phenyl)methoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-6-fluoro-4-(1-carboxy-1-(3-methoxy)phenyl)methoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6,8-difluoro-4-(1-carboxy-1-phenyl)methoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-dimethylamino-4-(1-phenyl-1-carboxy)methoxyquinoline;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-chloro-6-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-6-chloro-4-(1-phenyl-1-carboxy)methoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)carbonyl-3-methoxycarbonylpropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline;-   2-[1S-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline;-   2-[1S-(4-(methoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(1,1-dimethylethylaminocarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(furan-2-ylcarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(3-methylphenyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline;-   2-[1S-(4-(3-methylphenyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(phenyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline;    and-   2-[1S-(4-(phenyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline    in trifluoroacetic acid.

Of the compounds of formula (II) as set forth above in the Summary ofthe Invention, a preferred group of compounds is that group of compoundswherein:

-   m is 1;-   n is 1 or 2;-   R¹ is hydrogen, aryl, aralkyl, or alkoxycarbonyl;-   R² is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or    aralkoxycarbonylalkyl;-   R³ is heteroaryl optionally substituted by one or more substituents    selected from the group consisting of alkyl, halo, haloalkyl,    —R⁸—OR⁷, —R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂, and —R⁸—N(R⁷)₂;-   each R⁴ is independently selected from the group consisting of    hydrogen, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or    dialkylamino;-   R⁵ is hydrogen;-   R⁶ is hydrogen;-   each R⁷ is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; and-   each R⁸ is a bond or a straight or branched alkylene chain.

Of this preferred group of compounds, a preferred compound is2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)quinolinein trifluoroacetic acid.

Another preferred group of compounds of formula (II) is that group ofcompounds wherein:

-   m is 1;-   n is 1 or 2;-   R¹ is hydrogen, aryl, aralkyl, or alkoxycarbonyl;-   R² is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or    aralkoxycarbonylalkyl;-   R³ is heteroarylalkoxy, wherein the alkoxy radical in the    heteroarylalkoxy substituent is optionally substituted by one or    more substituents selected from the group consisting of halo and    —R⁸—C(O)OR⁷, and wherein the heteroaryl radical in the    heteroarylalkoxy substituent is independently optionally substituted    by one or more substituents selected from the group consisting of    alkyl, halo, haloalkyl, —R⁸—OR⁷, —R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂, and    —R⁸—N(R⁷)₂;-   each R⁴ is independently selected from the group consisting of    hydrogen, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or    dialkylamino;-   R⁵ is hydrogen;-   R⁶ is hydrogen;-   each R⁷ is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; and-   each R⁸ is a bond or a straight or branched alkylene chain.

Of this preferred group of compounds, preferred compounds are selectedfrom the group consisting of the following:

-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(5-methylisoxaxol-3-yl)methoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(2-methylthiazol-4-yl)methoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-methoxycarbonylpropyl]aminocarbonyl-4-(1-phenyl-1-ethoxycarbonyl-1-chloro)methoxyquinoline;-   2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-6-fluoro-4-(1-carboxy-1-thien-3-yl)methoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-chloro-7-methyl-4-(5-methylisoxazol-3-yl)methoxyquinoline;    and-   2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-chloro-7-methyl-4-(2-methylthiazol-4-yl)methoxyquinoline    in trifluoroacetic acid.    Preparation of the Compounds of the Invention

The compounds of the invention are prepared according to the methodsdescribed below in the following Reaction Schemes. It is understood thatthose compounds of the invention which are not specifically prepared inthe following Reaction Schemes may be prepared by similar syntheticprocesses with the appropriately substituted starting materials andreagents. It is also understood that during the preparation of thecompounds of the invention, as described below, additional reactivegroups (for example, hydroxy, amino or carboxy groups) on theintermediate compounds utilized in the preparation may be protected asneeded by the appropriate protecting group by treating the intermediatecompound prior to the desired reaction with the appropriate protectinggroup precursor by methods known to those of ordinary skill in the art.The protecting groups may then be removed as desired by methods known tothose of ordinary skill in the art, for example, by acidic or basichydrolysis. Such protecting groups and methods are described in detailin Greene, T. W. and Wuts, P. G. M., Protective Groups in OrganicSynthesis, 2nd Edition, 1991, John Wiley & Sons. Preferrednitrogen-protecting groups are “Boc” (t-butoxycarbonyl) and “CBZ”(benzyloxycarbonyl).

It will also be appreciated by those skilled in the art, although suchprotected derivatives of compounds of the invention as described abovein the Summary of the Invention, may not possess pharmacologicalactivity as such, they may be administered to a mammal having adisease-state characterized by thrombotic activity and thereaftermetabolized in the body to form compounds of the invention which arepharmacologically active. Such derivatives may therefore be described as“prodrugs”. All prodrugs of compounds of the invention are includedwithin the scope of the invention.

It is understood that in the following description, combinations ofsubstituents and/or variables of the depicted formulae are permissibleonly if such conbinations result in stable compounds which can beisolated by methods known to those of ordinary skill in the art.Transient compounds are indicated by brackets.

For purposes of convenience, the preparation of compounds of formula (I)(where R³ is aryl, aralkyl, aryloxy or aralkoxy) are only describedbelow. However, one of ordinary skill in the art would understand thatin order to prepare the corresponding compounds of formula (II), allthat one would need to do is replace the pertinent intermediates (suchas compounds of formula (J)) with the appropriate compound (such ascompounds of formula (J) where R^(3a) is heteroarylalkyl) and to adjustthe experimental parameters accordingly.

A. Preparation of Compounds of formula (D)

Compounds of formula (D) are intermediates used in the preparation ofthe compounds of the invention. They may be prepared as described belowin Reaction Scheme 1 wherein m, R¹, R², R⁵, and R⁶ are as describedabove in the Summary of the Invention; PG is a nitrogen-protectinggroup; and R^(1a) is hydrogen (or a nitrogen protecting group if R¹ ishydrogen):

Compounds of formulae (A) and (B) are commercially available, forexample, from Aldrich, or may be prepared according to methods known tothose of ordinary skill in the art, or by methods as described herein.

In general, compounds of formula (D) are prepared by first treating acompound of formula (B) in an aprotic solvent mixture, such astetrahydrofuran (THF) and methylene chloride, with a slightly excessmolar amount of a peptide coupling reaction additive, such as1-hydroxybenzotriazole (HOBT) and a slightly excess molar amount ofcoupling agent for amide formation, such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) at ambienttemperature. To this mixture is added a slightly excess molar amount ofa compound of formula (A) where R^(1a) is hydrogen and the resultingreaction mixture is allowed to stir overnight at ambient temperature.The compound of formula (C) is isolated from the reaction mixture bystandard isolation techniques, such as evaporation and extraction.

Depending on what PG is, the compound of formla (C) is then reducedunder standard hydrogenation conditions, such as treatment with pladiumover carbon under hydrogen or treated under standard hydrolysisconditions to form a compound of formula (D), which is isolated form thereaction mixture by filtration.

Alternatively, compounds of formula (A) where R¹ is hydrogen and R^(1a)is a nitrogen protecting group can be treated with the appropriatelysubsituted acid halide, carbamoyl halide or isocyanate to yield thecorresponding appropriately substituted compounds of formula (A), whichcan then be treated to standard deprotecting procedures to remove theR^(1a) nitrogen protecting group prior to being reacted with thecompound of formula (B) to form compounds of formula (C) and (D) whereinR¹ is as described above in the Summary of the Invention.

B. Preparation of Compounds of formula (H)

Compounds of formula (H) are intermediates in the preparation ofcompounds of formula (I) and are prepared as described below in ReactionScheme 2a wherein n is as described as above in the Summary of theInvention; R⁴ is as described above in the Summary of the Invention; andR¹⁰ is alkyl or aralkyl:

Compounds of formulae (E), and (F) are commercially available, forexample, from Aldrich, or may be prepared according to methods known tothose of ordinary skill in the art. Compounds of formula (G) and formula(H) may alternatively be prepared by methods disclosed in Great BritainPatent No. 1,334,705.

In general, compounds of formula (H) are prepared by first treating acompound of formula (F) in a protic solvent, such as methanol, with anequimolar amount of a compound of formula (E) with stirring at ambienttemperature for about 30 minutes to about an hour, preferably for about30 minutes. The solvent is removed by evaporation to form a residue.

To an aprotic polar solvent, such as diphenyl ether, heated to betweenabout 200° C. and about 250° C., preferably to about 250° C. is thenadded the residue and the temperature of the reaction mixture ismaintained at the high temperature for about 30 minutes to an hour,preferably for about 30 minutes, at which point the reaction mixture isallowed to cool to ambient temperature. The resulting precipitate iscollected and washed with a aprotic polar solvent, such as ether, whichis previously heated to below boiling temperature, to give compounds offormula (G). Further purification, for example, by dissolving themixture in a protic solvent at boiling temperature, such as methanol,and then allowing the mixture to cool to ambient temperature for aperiod of about 1 to about 2 days, preferably for about 2 days, yields acompound of formula (H), which is isolated from the reaction mixture bystandard techniques.

Alternatively, compounds of formula (D) as prepared above in ReactionScheme 1 can be reacted with compounds of the following structure:

which are commercially avaible or prepared by methods known to one ofordinary skill in the art, under standard acylation conditions to formadditional compounds of the invention.

A preferred method of making intermediates used in the preparation ofthe compounds of the invention which avoids the formation of undesiredregiosiomers with respect to the substitution on the quinoline ring isillustrated below in Reaction Scheme 2b wherein R^(4a) is alkyl, alkoxy,aralkoxy, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonylamino,di(alkylcarbonyl)amino, carboxyalkoxy, alkoxycarbonylalkoxy orheterocyclylalkoxy; X is iodo, chloro or bromo; and R¹⁰ is alkyl oraralkyl:

Compounds of formula (Fa) and formula (E) are commercially available, orcan prepared according to methods known to those of ordinary skill inthe art.

In general, compounds of formula (Gb) are prepared by first treating acompound of formula (Fa) with a reducing agent, such as tin (II)chloride dihydrate, under standard chemical reduction conditions, suchas in a protic solvent, to form the compound of formula (Fb), which isisolated from the reaction mixture by standard isolation techniques.

The compound of formula (Fb) in a protic solvent, such as methanol, isthen treated with a slightly excess molar amount of a compound offormula (E) at reflux temperatures for about 2 to about 4 hours,preferably for about 4 hours. The reaction mixture is then concentrated.An organic solvent is heated to a non-boiling point temperature ofbetween about 240° C. and about 260° C., and the concentrate is thenadded to the solvent. The temperature of the mixture is maintained atthe non-boiling point temperature for about 10 to 20 minutes, preferablyfor about 20 minutes. The reaction mixture is then cooled slowly toambient temperature and diluted with an organic solvent. The compound offormula (Ga) is isolated from the reaction mixture by standard isolationtechniques, such as filtration.

The compound of formula (Ga) is treated with a hydrolyzing agent understandard hydrolysis conditions and then treated under standard reducingconditions, such as hydrogen gas and palladium over carbon, to form acompound of formula (Gb).

Compounds of formula (Gb) may then be used instead of compounds offormula (H) in subsequent Reaction Schemes to prepare compounds of theinvention.

C. Preparation of Compounds of Formula (Ia)

Compounds of formula (Ia) are compound of the invention and are preparedas described below in Reaction Scheme 3 wherein m, n, R¹, R², R⁴, R⁵,and R⁶ are as defined above in the Summary of the Invention, R^(3a) isaryl or aralkyl, and X is halo:

Compounds of formulae (D) and (H) are prepared by methods disclosedherein. Compounds of formula (J) are commercially available, forexample, from Aldrich Co., or can be prepared according to methods knownto one of ordinary skill in the art.

In general, compounds of formula (Ia) are prepared by first treating acompound of formula (H) under standard Williamson synthesis conditions,such as in the presence of a base in an aprotic solvent, for example,cesium carbonate in N,N-dimethylformamide (“DMF”), with an equimolaramount of a compound of formula (J) at temperatures between aboutambient temperature and about 100° C. The reaction mixture is stirredfrom about 2 hours to about 10 hours, preferably for about 10 hours, toyield the compound of formula (K), which is then treated under standardhydrolysis conditions to yield the compound of formula (L).

The compound of formula (L) in an aprotic solvent mixture, for example,methylene chloride and DMF or methylene chloride and triethylamine, isthen treated with a slightly excess molar amount of a peptide couplingreaction additive, such as 1-hydroxybenzotriazole (“HOBT”) and aslightly excess molar amount a coupling agent for amide formation, suchas 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (“EDCI”) at ambienttemperature. An equimolar amount of a compound of formula (D) in anaprotic solvent, such as methylene chloride, is then added to thereaction mixture. The reaction mixture is stirred at ambient temperaturefor about 4 to about 12 hours, preferably for about 12 hours. Thecompound of formula (Ia) is then isolated from the reaction mixture bystandard isolation techniques, such as evaporation of the solvents,extraction and concentration.

If desired, compounds of formula (Ia) may be deprotected to yield thecorresponding free acid or free amine derivatives. Furthermore,compounds of formula (Ia) wherein R¹ is a nitrogen-protecting group,such as an alkyl carbonyl, can be hydrolyzed under standard acidhydrolysis conditions to yield the corresponding compound of formula(Ia) wherein R¹ is hydrogen, which can then be treated with theappropriately substituted acid halide, carbamoyl halide or isocyanate toyield the appropriately substituted R¹ compound of formula (Ia).

D. Preparation of Compounds of Formula (Ib)

Compounds of formula (Ib) are compounds of the invention and areprepared as described below in Reaction Scheme 4 wherein n, R¹, R², R⁴,R⁵ and R⁶ are as described above in the Summary of the Invention, R^(3a)is aryl or aralkyl and X is halo:

Compounds of formula (D) are prepared as described herein or may beprepared by methods known to one of ordinary skill in the art. Compoundsof formula (H) are prepared as described herein or may be prepared bymethods known to one of ordinary skill in the art, such as those foundin Great Britain Patent No. 1,334,705.

In general, compounds of formula (Ib) are prepared by first treating asuspension of a compound of formula (H) in an aprotic solvent mixture,such as methylene chloride and DMF, with a slightly excess molar amountof a peptide coupling reaction additive, such as 1-hydroxybenzotriazole(“HOBT”) and a slightly excess molar amount a coupling agent for amideformation, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide(“EDCI”) at ambient temperature. An equimolar amount of a compound offormula (D) in an aprotic solvent, such as methylene chloride, is thenadded to the reaction mixture. The reaction mixture is stirred atambient temperature for a period of time of between about 4 hours andabout 12 hours, preferably for a period of time of between about 6 hoursand about 12 hours. The compound of formula (M) is then isolated fromthe reaction mixture by standard isolation techniques, such asevaporation of the solvents, extraction and concentration.

The compound of formula (M) is then treated under standard Williamsonsynthesis conditions, such as in the presence of base in an aproticsolvent, for example, cesium carbonate in acetonitrile:DMF, with an anequimolar amount of a compound of formula (J) at a temperature ofbetween about ambient temperature and 100° C. The reaction mixture isstirred for a period of time of between 30 minutes and about 10 hours,preferably for abou 30 minutes. The compound of formula (Ib) is thenisolated from the reaction mixture by standard isolation techniques,such as organic extraction and concentration.

If desired, compounds of formula (Ib) can be treated under standardhydrolysis conditions to yield the corresponding free amine or acid.

E. Preparation of Compounds of Formulae (Ic), (Id) and (Ie)

Compounds of formulae (Ic), (Id) and (Ie) are compounds of the inventionand are prepared as described below in Reaction Scheme 5 wherein m, n,R¹, R², R⁴, R⁵ and R⁶ are as described above in the Summary of theInvention, X is halo, R^(3b) is aryl or aralkyl, and R^(3c) isheteroaryl:

Compounds of formulae (H) and (D) are prepared as described herein orcan be prepared according to methods known to one of ordinary skill inthe art. Compounds of formulae (P), (Q) and (R) are commerciallyavailable, for example, from Aldrich Chemical Co., or can be preparedaccording to methods known to one of ordinary skill in the art.

In general, compounds of formulae (Ic), (Id) and (Ie) are prepared byfirst treating a compound of formula (H) with a halogenating agent, suchas phosphorus pentachloride or phosphorus oxychloride, under standardhalogenating conditions. The compound of formula (N) is isolated fromthe reaction mixture by standard isolation techniques.

The compound of formula (N) is then treated with a compound of formula(D) under standard peptide coupling conditions, as described herein, toyield a compound of formula (O), which is isolated from the reactionmixture by standard isolation techniques.

The compound of formula (O) in an polar aprotic solvent, such as DMSO,in the presence of a base, such as cesium carbonate, is then treatedwith a compound of formula (P). The resulting reaction mixture is heatedto a temperature of between about 40° C. and about 60° C., preferably atabout 60° C. for a period of time of between about 4 hours and about 16hours, preferably for about 16 hours. The compound of formula (Ic) isthen isolated from the reaction mixture by standard isolationtechniques, such as filtration and purification by preparative HPLC. Ifdesired, the compound of formula (Ic) can be treated under standardhydrolysis conditions to further yield the corresponding free acid oramine.

Alternatively, a mixture of a compound of formula (O) and a compound offormula (Q) in a polar aprotic solvent, such as DMSO, is heated to atemperature of between about 80° C. and 105° C., preferably to about100° C., for a period of time of between about 6 hours and 18 hours,preferably for about 18 hours. The compound of formula (Id) is thenisolated from the reaction mixture by standard isolation techniques,such as purification by reverse phase HPLC. If desired, the compound offormula (Id) can be hydrolyzed under standard hydrolysis conditions tofurther yield the corresponding amine or acid.

Alternatively, a compound of formula (O) is treated with a compound offormula (R) under standard boronic acid/palladium coupling conditions toyield the corresponding compound of formula (Ie), which is isolated fromthe reaction mixture by standard isolation techniques. If desired, thecompound of formula (Ie) can be hydrolyzed under standard hydrolysisconditions to further yield the corresponding amine or acid.

Alternatively, compounds of formula (Gb) may be used in the aboveReaction Schemes in place of the compounds of formula (H).

All compounds of the invention as prepared above which exist in freebase or acid form may be converted to their pharmaceutically acceptablesalts by treatment with the appropriate inorganic or organic base oracid. Salts of the compounds prepared above may be converted to theirfree base or acid form by standard techniques.

The following specific preparations and examples are provided as a guideto assist in the practice of the invention, and are not intended as alimitation on the scope of the invention.

PREPARATION 1 Compounds of Formula (D)

A. To a solution of N-benzyloxycarbonyl-L-glutamic acid y-t-butyl ester(24.4 g, 72.3 mmol) in tetrahydrofuran (“THF”) (400 mL) and CH₂Cl₂ (100mL) was added 1-hydroxybenzotriazole (“HOBT”) (10.7 g, 79.5 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (“EDCI”) (15.3 g, 79.5mmol). After 5 minutes, 1-ethoxycarbonylpiperazine (11.7 mL, 79.5 mmol)was added and the reaction was stirred overnight. The reaction mixturewas evaporated in vacuo to afford an oil, which was dissolved in ethylacetate, and washed with saturated NaHCO₃, 1M HaHSO₄ and brine. Theorganic layer was evaporated in vacuo to4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine(40.7 g), as an oil that was used without further purification. To4-ethoxycarbonyl-1-(1-(benzyloxycarbonyl)amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazinein MeOH (100 mL) was added 10% Pd/C (1 g) and the mixture was shakenunder 50 psi H₂ overnight. The reaction was filtered and stripped to4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine(25 g, 99%) and used without further purification; NMR (CDCl₃) 1.25 (t,3), 1.43 (s, 9), 2.55 (m, 1), 1.90 (m, 1), 2.37 (m, 1), 2.55 (m, 1),3.40–3.70 (m, 8), 3.80 (m, 1), 4.18 (q, 2) ppm.

B. In a similar manner, other compounds of formula (D) were prepared.

-   4-ethoxycarbonyl-1-(aminomethyl)carbonylpiperazine;-   4-ethoxycarbonyl-1-(1-amino-3-carboxypropyl)carbonylpiperazine;-   4-ethoxycarbonyl-2-methyl-1-(aminomethyl)carbonylpiperazine;-   4-ethoxycarbonyl-3-methyl-1-(aminomethyl)carbonylpiperazine;-   4-ethoxycarbonyl-1-(1-amino-5-((2-chlorobenzyloxy)carbonylamino)pentyl)carbonylpiperazine;-   4-ethoxycarbonyl-1-(1-amino-2-(benzyloxycarbonyl)ethyl)carbonylpiperazine;-   4-ethoxycarbonyl-1-(1-amino-2-phenylethyl)carbonylpiperazine;-   4-ethoxycarbonyl-1-(1-amino-2-methylpropyl)carbonylpiperazine;-   4-ethoxycarbonyl-1-(1-amino-2-carboxyethyl)carbonylpiperazine; and-   4-ethoxycarbonyl-1-(1,5-diaminopentyl)carbonylpiperazine.

C. Alternatively, N-benzyloxycarbonyl-L-glutamic acid y-t-butyl ester(34 g, 100 mmol) and EDCI (22 g, 110 mmol), HOBT (15 g, 110 mmol) werecombined in 800 mL CH₂Cl₂ with triethylamine (24 mL, 172 mmol). Theresulting reaction mixture was stirred at ambient temperature for 20minutes, then 1-ethoxycarbonylpiperazine (18 g, 120 mmol) was added. Theresulting mixture was stirred at ambient temperature for 15 hours. Thereaction mixture was then washed with water, 2N NaHSO₄, and brine, thenconcentrated in vacuo to afford an oil, which was purified by flashcolumn chromatography on silica gel (acetate/hexane=1/1) to afford4-ethoxycarbonyl-1-(1-(benzyloxycarbonyl)amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine(40 g).4-ethoxycarbonyl-1-(1-(benzyloxycarbonyl)amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine(40 g) was dissolved in 200 mL of MeOH, 2 g Pd/C(10%) was added andhydrogenated at 50 psi for 1 hour. Regular work up afforded4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine(25 g).

PREPARATION 2 Compounds of Formula (G)

A. To a solution of m-toludine (20.0 g, 0.186 mol) in methanol (300 mL),dimethyl acetylenedicarboxylate (26.42 g, 0.186 mol) was added drop-wiseand the reaction mixture was stirred at ambient temperature for 30minutes. The solvent was removed by evaporation and the residue wasadded to stirred diphenyl ether (150 ml), which has been preheated to250° C. After 30 minutes, the mixture was cooled to ambient tempertureand the resulting precipitate was collected and washed with hotpetroleum ether (1.5 L) to give a mixture (27.0 g) of5-methyl-4-hydroxy-2-methoxycarbonylquinoline and7-methyl-4-hydroxy-2-methoxycarbonylquinoline. The mixture was dissolvedin boiling methanol (1.3 L) and kept at ambient temperature for two daysto afford (6.45 g, 16%) of7-methyl-4-hydroxy-2-methoxycarbonylquinoline, NMR (DMSO-d₆) 2.40 (s,3), 3.92 (s, 3), 6.56 (s, 1), 7.16 (d, 1), 7.68 (s, 1), 7.94 (d, 1) ppm.

B. In a similar manner, other compounds of formula (G) were prepared asfollows:

-   8-methoxy-4-hydroxy-2-methoxycarbonylquinoline;-   5-amino-4-hydroxy-2-methoxycarbonylquinoline;-   5-nitro-4-hydroxy-2-methoxycarbonylquinoline;-   5-carboxymethylamino-4-hydroxy-2-methoxycarbonylquinoline;-   7-chloro-4-hydroxy-2-methoxycarbonylquinoline;-   5-di(acetyl)amino-4-hydroxy-2-methoxycarbonylquinoline;-   5-acetylamino-4-hydroxy-2-methoxycarbonylquinoline;-   5,7-dichloro-4-hydroxy-2-methoxycarbonylquinoline;-   6-chloro-4-hydroxy-2-methoxycarbonylquinoline;-   6-nitro-4-hydroxy-2-methoxycarbonylquinoline;-   6-amino-4-hydroxy-2-methoxycarbonylquinoline;-   7-benzyloxy-4-hydroxy-2-methoxycarbonylquinoline;-   4,7-dihydroxy-2-methoxycarbonylquinoline;-   7-prop-1-oxy-4-hydroxy-2-methoxycarbonylquinoline;-   7-carboxymethoxy-4-hydroxy-2-methoxycarbonylquinoline;-   7-diethylaminoethoxy-4-hydroxy-2-methoxycarbonylquinoline;-   7-methoxy-4-hydroxy-2-methoxycarbonylquinoline;-   7-(2-(4-hydroxy-2-carboxypyrrolidinyl)ethoxy)-4-hydroxy-2-methoxycarbonylquinoline;-   8-methyl-4-hydroxy-2-methoxycarbonylquinoline;-   6-diethylaminomethyl-4-hydroxy-2-methoxycarbonylquinoline;-   6-benzyloxy-4-hydroxy-2-methoxycarbonylquinoline;-   4,6-dihydoxy-2-methoxycarbonylquinoline;-   6-carboxymethoxy-4-hydroxy-2-methoxycarbonylquinoline;-   6-ethoxy-4-hydroxy-2-methoxycarbonylquinoline;-   6-methoxy-4-hydroxy-2-methoxycarbonylquinoline;-   6-prop-2-oxy-4-hydroxy-2-methoxycarbonylquinoline;-   7-fluoro-4-hydroxy-2-methoxycarbonylquinoline;-   7-trifluoromethyl-4-hydroxy-2-methoxycarbonylquinoline;-   7-hydroxymethyl-4-hydroxy-2-methoxycarbonylquinoline;-   7-cyano-4-hydroxy-2-methoxycarbonylquinoline;-   7-nitro-4-hydroxy-2-methoxycarbonylquinoline;-   6-carboxy-4-hydroxy-2-methoxycarbonylquinoline;-   7-trifluoromethoxy-4-hydroxy-2-methoxycarbonylquinoline;-   6-trifluoromethoxy-4-hydroxy-2-methoxycarbonylquinoline;-   7-acetyl-4-hydroxy-2-methoxycarbonylquinoline;-   5-ethoxycarbonyl-4-hydroxy-2-methoxycarbonylquinoline;-   6-ethyl-4-hydroxy-2-methoxycarbonylquinoline;-   7-carboxy-4-hydroxy-2-methoxycarbonylquinoline;-   6-aminocarbonyl-4-hydroxy-2-methoxycarbonylquinoline;-   6,7-dimethoxy-4-hydroxy-2-methoxycarbonylquinoline;-   6-chloro-7-methyl-4-hydroxy-2-methoxycarbonylquinoline;-   6-fluoro-7-methyl-4-hydroxy-2-methoxycarbonylquinoline;-   6-fluoro-4-hydroxy-2-methoxycarbonylquinoline;-   6-fluoro-7-chloro-4-hydroxy-2-methoxycarbonylquinoline;-   7-bromo-4-hydroxy-2-methoxycarbonylquinoline;-   6,7-dimethyl-4-hydroxy-2-methoxycarbonylquinoline;-   6-methoxy-7-methyl-4-hydroxy-2-methoxycarbonylquinoline;-   6-methoxy-7-chloro-4-hydroxy-2-methoxycarbonylquinoline;-   6-chloro-8-fluoro-4-hydroxy-2-methoxycarbonylquinoline;-   6,7-dichloro-4-hydroxy-2-methoxycarbonylquinoline;-   6,8-difluoro-4-hydroxy-2-methoxycarbonylquinoline;-   6,7-difluoro-4-hydroxy-2-methoxycarbonylquinoline;-   6-dimethylamino-4-hydroxy-2-methoxycarbonylquinoline;-   5-fluoro-6-methyl-4-hydroxy-2-methoxycarbonylquinoline;-   6-methyl-7-chloro-4-hydroxy-2-methoxycarbonylquinoline;-   6-acetyl-4-hydroxy-2-methoxycarbonylquinoline;-   6-methylthio-4-hydroxy-2-methoxycarbonylquinoline;-   4,5-dihydroxy-2-methoxycarbonylquinoline;-   7-ethyl-4-hydroxy-2-methoxycarbonylquinoline;-   5-methyl-4-hydroxy-2-methoxycarbonylquinoline;-   5-hydroxymethoxy-4-hydroxy-2-methoxycarbonylquinoline;-   5-(3-ethoxycarbonylpropoxy)-4-hydroxy-2-methoxycarbonylquinoline;    and-   5-(3-carboxypropoxy)-4-hydroxy-2-methoxycarbonylquinoline.

PREPARATION 3 Compounds of Formula (H)

A. 7-methyl-4-hydroxy-2-methoxycarbonylquinoline (6.45 g, 30.14 mmol)was suspended in MeOH (150 mL) and water (100 mL), and LiOH (3.08 g,75.5 mmol) was added and stirred at ambient temperature for 2 hours. Themethanol was evaporated in vacuo and residue was crystallized byaddition of 2N hydrochloric acid. The resulting solid was filtered,washed with water and dried to afford7-methyl-4-hydroxy-2-carboxyquinoline (6.0 g, 98%), NMR (DMSO-d₆) 2.40(s, 3), 6.68 (s, 1), 7.22 (d, 1), 7.68 (s, 1), 7.96 (d, 1).

B. In a similar manner, the following compounds of formula (H) wereprepared:

-   8-methoxy-4-hydroxy-2-carboxyquinoline;-   5-amino-4-hydroxy-2-carboxyquinoline;-   5-nitro-4-hydroxy-2-carboxyquinoline;-   5-carboxymethylamino-4-hydroxy-2-carboxyquinoline;-   7-chloro-4-hydroxy-2-carboxyquinoline;-   5-di(acetyl)amino-4-hydroxy-2-carboxyquinoline;-   5-acetylamino-4-hydroxy-2-carboxyquinoline;-   5,7-dichloro-4-hydroxy-2-carboxyquinoline;-   6-chloro-4-hydroxy-2-carboxyquinoline;-   6-nitro-4-hydroxy-2-carboxyquinoline;-   6-amino-4-hydroxy-2-carboxyquinoline;-   7-benzyloxy-4-hydroxy-2-carboxyquinoline;-   4,7-dihydroxy-2-carboxyquinoline;-   7-prop-1-oxy-4-hydroxy-2-carboxyquinoline;-   7-carboxymethoxy-4-hydroxy-2-carboxyquinoline;-   7-diethylaminoethoxy-4-hydroxy-2-carboxyquinoline;-   7-methoxy-4-hydroxy-2-carboxyquinoline;-   7-(2-(4-hydroxy-2-carboxypyrrolidinyl)ethoxy)-4-hydroxy-2-carboxyquinoline;-   8-methyl-4-hydroxy-2-carboxyquinoline;-   6-diethylaminomethyl-4-hydroxy-2-carboxyquinoline;-   3-methyl-4-hydroxy-2-carboxyquinoline;-   6-benzyloxy-4-hydroxy-2-carboxyquinoline;-   4,6-dihydoxy-2-carboxyquinoline;-   6-carboxymethoxy-4-hydroxy-2-carboxyquinoline;-   6-ethoxy-4-hydroxy-2-carboxyquinoline;-   6-methoxy-4-hydroxy-2-carboxyquinoline;-   6-prop-2-oxy-4-hydroxy-2-carboxyquinoline;-   7-fluoro-4-hydroxy-2-carboxyquinoline;-   7-trifluoromethyl-4-hydroxy-2-carboxyquinoline;-   7-hydroxymethyl-4-hydroxy-2-carboxyquinoline;-   7-cyano-4-hydroxy-2-carboxyquinoline;-   7-nitro-4-hydroxy-2-carboxyquinoline;-   2,6-dicarboxy-4-hydroxyquinoline;-   7-trifluoromethoxy-4-hydroxy-2-carboxyquinoline;-   6-trifluoromethoxy-4-hydroxy-2-carboxyquinoline;-   7-acetyl-4-hydroxy-2-carboxyquinoline;-   5-ethoxycarbonyl-4-hydroxy-2-carboxyquinoline;-   6-ethyl-4-hydroxy-2-carboxyquinoline;-   2,7-dicarboxy-4-hydroxyquinoline;-   6-aminocarbonyl-4-hydroxy-2-carboxyquinoline;-   6,7-dimethoxy-4-hydroxy-2-carboxyquinoline;-   6-methyl-7-chloro-4-hydroxy-2-carboxyquinoline;-   6-chloro-7-methyl-4-hydroxy-2-carboxyquinoline;-   6-fluoro-7-methyl-4-hydroxy-2-carboxyquinoline;-   6-fluoro-4-hydroxy-2-carboxyquinoline;-   6-fluoro-7-chloro-4-hydroxy-2-carboxyquinoline;-   7-bromo-4-hydroxy-2-carboxyquinoline;-   6,7-dimethyl-4-hydroxy-2-carboxyquinoline;-   6-methoxy-7-methyl-4-hydroxy-2-carboxyquinoline;-   6-methoxy-7-chloro-4-hydroxy-2-carboxyquinoline;-   6-chloro-8-fluoro-4-hydroxy-2-carboxyquinoline;-   6,7-dichloro-4-hydroxy-2-carboxyquinoline;-   6,8-difluoro-4-hydroxy-2-carboxyquinoline;-   6,7-difluoro-4-hydroxy-2-carboxyquinoline;-   6-dimethylamino-4-hydroxy-2-carboxyquinoline;-   5-fluoro-6-methyl-4-hydroxy-2-carboxyquinoline;-   6-acetyl-4-hydroxy-2-carboxyquinoline;-   6-methylthio-4-hydroxy-2-carboxyquinoline;-   4,5-dihydroxy-2-carboxyquinoline;-   5-hydroxymethoxy-4-hydroxy-2-carboxyquinoline;-   7-methyl-4-hydroxy-2-carboxyquinoline;-   5-methyl-4-hydroxy-2-carboxyquinoline;-   5-(3-ethoxycarbonylpropoxy)-4-hydroxy-2-carboxyquinoline; and-   5-(3-carboxypropoxy)-4-hydroxy-2-carboxyquinoline.

PREPARATION 4 Compounds of Formulae (Fb), (Ga) and (Gb)

A. To a solution of SnCl₂.H₂O (140 g, 0.62 mol) in ethanol (350 mL) wasadded a solution of 2,6-dichloro-3-nitrotoluene (25 g, 0.12 mol) inethanol (50 mL). The reaction mixture was refluxed for 1 hour. Thereaction mixture was concentrated under reduced pressure. The residuewas dissolved in water (100 mL), pH was adjusted to approximately pH 12with 1N NaOH solution and extracted with ethyl acetate. The ethylacetate layer was washed with brine, dried over sodium sulfate, andconcentrated to afford 2,6-dichloro-3-aminotoluene (21 g, 98%); NMR(CDCl₃) 2.42 (s, 3), 6.62 (d, 1), 7.14 (d, 1) ppm.

B. To a solution of 2,6-dichloro-3-aminotoluene (20.5 g, 0.11 mol) inmethanol (300 mL) was added dimethyl acetylenedicarboxylate (15 mL, 0.12mol) and the reaction mixture was refluxed for 2 hours. The reactionmixture was concentrated under reduced pressure to a yellow solid.Diphenyl ether (350 mL) was heated to 230–240° C., and the yellow solidwas added to it. The temperature was maintained at 230–240° C. for 20minutes and the reaction mixture was cooled slowly to ambienttemperature and diluted with petroleum ether (1L). The solid wasfiltered and washed with hot ethyl acetate to afford a brown solid,2-(methoxycarbonyl)-4-oxo-6,8-dichloro-7-methylquinoline (28.5 g, 85%);NMR (CDCl₃) 2.62 (s, 3), 4.04 (s, 3), 7.02 (s, 1), 8.24 (s, 1) ppm.

C. 2-(Methoxycarbonyl)-4-oxo-6,8-dichloro-7-methylquinoline (28.5 g,99.6 mmol) was suspended in methanol (1 L) and a solution of LiOH.H₂O(20.5 g, 0.5 mol) in water (200 mL) was added to the solution. Theresulting reaction mixture was stirred at ambient temperature for 0.5hours. Pd/C (5.8 g) was added to the reaction mixture and the resultingreaction mixture was shaken under 50 Psi hydrogen overnight. Thereaction mixture was filtered, concentrated under reduced pressure toremove methanol, diluted with water (300 mL) and the pH was adjusted tobetween pH 3 and pH 4 by 2N HCl. The precipitate was collected byfiltration, washed with water and dried to afford a white solid,2-carboxy-4-oxo-7-methylquinoline (20 g, 90%); NMR (DMSO-d₆) 2.40 (s,3), 6.60 (s, 1), 7.20 (d, 1), 7.68 (s, 1), 7.96 (d, 1) ppm.

D. Alternatively, to a solution of 4-chloro-3-methyl aniline (20.0 g,0.141 mol) in MeOH (400 mL) was added drop-wise dimethylacetylenedicarboxylate (21.07 g, 0.148 mol). The reaction mixture wasstirred at ambient temperature for 30 minutes. The solvent was removedby evaporation and the residue was added to stirred diphenyl ether (300mL), which has been preheated to 250° C. After 30 minutes, the mixturewas cooled to ambient temperature and the resulting precipitate wascollected and washed with 1 L of hot petroleum ether to give a mixture(29.0 g) of 2-methoxycarbonyl-6-chloro-7-methyl-4-oxoquinoline and2-methoxycarbonyl-6-chloro-5-methyl-4-oxoquinoline as a gray solid. Themixture was dissolved in boiling methanol (1 L) and filtered hot. Thecollected solids were boiled in 1.2 L of methanol and filtered hot toafford (6.45 g, 16%) of2-methoxycarbonyl-6-chloro-7-methyl-4-oxoquinoline: ¹H NMR (DMSO-d₆)2.41 (s, 3), 3.92 (s, 3), 6.58 (s, 1), 7.86 (s, 1), 7.96(s, 1) ppm.

E. 2-Methoxycarbonyl-6-chloro-7-methyl-4-oxoquinoline (7.00 g, 28.00mmol) was suspended in 300 mL of MeOH and 100 mL of water. Lithiumhydroxide (3.40 g, 90 mmol) was added and the reaction was stirred atroom temp for 2 hours. The methanol was evaporated in vacuo and theproduct was crystallized by addition of 2N hydrochloric acid. The solidwas filtered, washed with water and dried to afford 5.9 g (88%) of2-carboxy-6-chloro-7-methyl-4-oxoquinoline: H NMR (DMSO-d₆) 2.40 (s, 3),6.60 (s, 1), 7.84 (s, 1), 7.98 (s, 1) ppm.

PREPARATION 5 Compounds of Formulae (K) and (L)

A. 2-carboxy-4-hydroxyquinoline (5 g, 1.0 eq) was dissolved in 50 mLDMF. Cesium carbonate (20 g, 2.3 eq) was added to the solution and theresulting reaction mixture was heated at 50° C. for 20 minutes. Benzylbromide (10 g, 2.1 eq) was added. The resulting reaction mixture wasstirred at 50° C. for 1 hour. Then the reaction mixture was poured into500 mL ice-water, the precipitate was collected by filtration, and driedin vacuo to afford 2-benzyloxycarbonyl-4-benzyloxyquinoline (9.1 g).2-benzyloxycarbonyl-4-benzyloxyquinoline (9.0 g) was dissolved in 50 mLTHF, and 2 N LiOH solution (20 mL) was added, and the resulting reactionmixture was stirred at ambient temperature for 2 hours. The solvent wasthen removed in vacuo, and the residue acidified by the addition of 2NNaHSO₄ to pH 3–4. The white precipitate was collected to afford2-carboxy-4-benzyloxyquinoline (7.2 g), which was used without furtherpurification.

B. In a similar manner, other compounds of formula (K) and (L) wereprepared.

PREPARATION 6 Compounds of Formula (M)

A. To a suspension of 2-carboxy-6-chloro-7-methyl-4-oxoquinoline (7.5 g,31.69 mmol) in dichloromethane:DMF (350 mL, 2.5:1) was added HOBT (5.13g, 38 mmol) and EDCI (7.25 g, 38 mmol) and the reaction mixture wasstirred for 10 minutes. A solution of4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine(10.8 g, 31.64 mmol) in 50 mL dichloromethane was added. The reactionwas stirred at ambient temperature for 6 hours. The solvent wasevaporated in vacuo and the residue was partitioned in ethyl acetate andwater. The aqueous layer was extracted with ethyl acetate. The combinedorganic layers were washed with water, brine and concentrated to affordan off-white foam that was purified by flash chromatography (2% methanolin dichloromethane ) to afford2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-7-methyl-6-chloro-4-hydroxyquinolineas a white foam, (14.4 g, 80%).

B. In a similar manner, other compounds of formula (M) were prepared.

C. Alternatively, 2-carboxy-4-hydroxyoxoquinoline (640 mg, 3.2 mmol),EDCI (674 mg, 3.5 mmol), and HOBT (525 mg, 3.5 mmol) were combined in 20mL CH₂Cl₂ with triethylamine (0.67 mL, 4.8 mmol). The resulting reactionmixture was stirred at ambient temperature for 10 minutes, then4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)-carbonylpiperazine(1.1 g, 3.3 mmol) was added. The resulting mixture was stirred atambient temperature for 2 hours. The reaction mixture was washed withwater, 2N NaHSO₄, and brine, then concentrated in vacuo to afford anoil, which was purified by flash column chromatography on silica gel toafford2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-hydroxyquinoline(1.28 g).

D. Alternatively, to a solution of2-carboxy-6-chloro-8-fluoro-4-hydroxyquinoline (1.0 g , 4.14 mmol) inDMF (50 mL) was added diisopropylethyl amine (3.0 eq., 2.2 mL). Themixture was stirred at ambient temperature for 30 minutes. EDCI (1.2eq., 969 mg ) and HOBT (1.1 eq., 628 mg) were added, followed by theaddition of4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine(1.493 g, 1.05 eq.) and the mixture was stirred overnight at ambienttemperature. The solvent, DMF, was evaporated in vacuo to afford a crudeproduct, which was dissolved in ethyl acetate, washed with saturatedNaHCO₃, 1M NaHSO₄ and brine. The organic layer was evaporated. Flashcolumn chromatography with 1%–3% MeOH in CH₂Cl₂ afforded the couplingproduct,2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-6-chloro-8-fluoro-4-hydroxyquinolinein acetic acid, (2.01 g).

PREPARATION 7 Compounds of Formula (N)

A. To 20 mL POCl₃ was added 2-carboxy-7-methyl-4-hydroxyquinoline (2.5g, 12.3 mmol) and PCl₅ (11.5 g, 55 mmol). The mixture was heated to 130°C. for 3 hours. The reaction mixture was cooled and poured onto ice. Thesolution was neutralized with solid NaOH and adjusted to pH 11 withsolid KOH. The tan precipitate was filtered, slurried in 250 mL waterand adjusted to pH 2 with concentrated HCl. The resultant solid wasfiltered and dried to afford 2-carboxy-7-methyl-4-chloroquinoline (1.34g, 50%).

B. In a similar manner, other compounds of formula (N) were prepared:

PREPARATION 8 Compounds of Formula (O)

A. A solution of4-ethoxycarbonyl-1-(1-amino-3-(methoxycarbonyl)propyl)-carbonylpiperazine(0.97 g, 3.23 mmol), 4-chloro-2-carboxyquinoline (0.67 g, 3.23 mmol),EDCI (0.68 g, 3.55 mmol) and HOBT (0.48 g, 3.55 mmol) was combined in 30mL of THF. The reaction mixture was stirred overnight at ambienttemperature. The reaction was diluted with ethyl acetate and washed withwater. The organic layer was concentrated to give a dark oil (0.87 g)that was purified by flash chromotography through silica gel with 2:1ethyl acetate-hexanes to provide2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(methoxycarbonyl)propyl]aminocarbonyl-4-chloroquinoline,(0.46 g).

B. A solution of2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(methoxycarbonyl)propyl]aminocarbonyl-4-chloroquinoline(0.15 g, 0.313 mmol) was dissolved in 5 mL THF and LiOH (0.25 M, 1.9 mL,0.47 mmol) was added. The reaction was stirred for 2 hours. The reactionwas concentrated to an oil, acidified with 10% HCl, extracted into ethylacetate, and concentrated to provide pure2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-chloroquinoline(167 mg): ¹H NMR 1.20 (t, 3), 1.90 (m, 1), 2.05 (m, 1), 2.35 (m, 2),3.35–3.60 (m, 8), 3.65 (m, 2), 4.05 (q, 2), 5.07 (m, 1), 7.95 (m, 1),8.02 (m, 1), 8.23 (s, 1), 8.30 (m, 1), 8.98 (m, 1) ppm.

C. Alternatively, to a solution of 2-carboxy-7-methyl-4-chloroquinoline(1.3 g, 5.9 mmol) in THF (50 mL) at 0° C. was added N-methylmorpholine(1.7 mL, 14.7 mmol) followed by iso-butylchloroformate (0.84 mL, 6.45mmol). The reaction was stirred for 0.5 hours, then4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine(2.0 g, 5.9 mmol) was added and the reaction was warmed to ambienttemperature. Aqueous work-up afforded a crude product. The sample waspurified by flash chromatography through silica gel (3:2 ethylacetate:hexanes) to afford2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-7-methyl-4-chloroquinoline(0.95 g, 30%).

D. In a similar manner, other compounds of formula (O) were prepared:

EXAMPLE 1 Compounds of Formula (Ia)

A. 2-Carboxy-4-benzyloxyquinoline (800 mg, 1.0 eq) and EDCI (680 mg, 1.1eq), HOBT (520 mg, 1.1 eq) were combined in 25 mL methylene chloridewith triethylamine (1.0 mL, 3.2 eq). The resulting reaction mixture wasstirred at ambient temperature for 10 minutes, and then4-ethoxycarbonyl-1-(1-amino-3-(benzyloxycarbonyl)propyl)carbonylpiperazinewas added (1.0 g, 1.25 eq). The resulting reaction mixture was stirredat ambient temperature for 12 hours. The reaction mixture was thenwashed with water, 2N NaHSO₄, and brine, then concentrated in vacuo toafford an oil, which was purified by flash column chromatography onsilica gel to afford2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-benzyloxycarbonylpropyl]aminocarbonyl-4-benzyloxyquinoline(1.6 g). Then 50 mg of2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-benzyloxycarbonylpropyl]aminocarbonyl-4-benzyloxyquinolinewas dissolved in 2 mL MeOH and 1 mL water, and lithium hydroxide added(10 mg), and the resulting mixture was stirred at ambient temperaturefor 2 hours. Standard work-up afforded2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-benzyloxyquinoline(30 mg).

B. In a similar manner, the following compounds of formula (Ia) wereprepared:

-   2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-benzyloxyquinoline;-   2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline;-   2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-benzyloxycarbonylpropyl]aminocarbonyl-4-benzyloxy-8-methoxyquinoline;    and-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-benzyloxy-8-methoxyquinoline.

EXAMPLE 2 Compounds of Formula (Ib)

A. Methyl α-bromophenylacetate (0.22 g, 1 mmol) was added to a solutionof2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]-aminocarbonyl-7-methyl-6-chloro-4-hydroxyquinoline(0.42 g, 0.74mmol) and cesium carbonate (0.48 g, 1.48 mmol) in 10 mLCH₃CN/DMF (4:1) and stirred at 40° C. for 30 minutes. The reactionmixture was filtered, evaporated, dissolved in ethyl acetate, washedwith water, brine and concentrated to afford2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-7-methyl-6-chloro-4-(1-phenyl-1-methoxycarbonyl)methoxyquinolineas a reddish oil (0.55 g). The crude material was carried on to the nextstep.

B. A solution of2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-7-methyl-6-chloro-4-(1-phenyl-1-methoxycarbonyl)methoxyquinoline(0.55 g, ) in MeOH (5 mL) was saponified by reaction with LiOH (3 mL,0.25 M) for 40 minutes. The solvent was evaporated and the residue waspurified by preparative HPLC to afford2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-7-methyl-6-chloro-4-(1-phenyl-1-carboxy)methoxyquinolineas two pure diastereomers (A) and (B) as white solids (A 180 mg, B 190mg): ¹H NMR of B (DMSO-d₆) 1.18 (t, 3), 1.20 (s, 9), 1.82 (m, 1), 2.0(m, 1), 2.22 (m, 2), 2.54 (s, 3), 3.46 (m, 8), 4.04 (q, 2), 5.00 (m, 1),6.38 (s, 1), 7.2 (m, 3), 7.45 (s, 1), 7.62 (m, 2), 8.04 (s, 1), 8.10 (s,1), 8.86 (d, 1) ppm.

C. A solution of2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-7-methyl-6-chloro-4-(1-phenyl-1-carboxy)methoxyquinoline(190 mg, 0.23 mmol) in 50% TFA-dichloromethane (6 mL) was stirred atambient temperature for 1 hour. The solvent was evaporated and purifiedby preparative HPLC to afford2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-6-chloro-4-(1-phenyl-1-carboxy)methoxyquinolinein trifluoroacetic acid; as a white solid (116 mg, 66%) as a TFA salt:¹H NMR (DMSO-d₆) 1.12 (t, 3), 1.85 (m, 1), 2.05 (m, 1), 2.30 (m, 2),2.55 (s, 3), 3.45 (m, 6), 3.65 (m, 2), 4.05 (q. 2), 5.02 (m, 1), 6.39(s, 1), 7.45 (m, 3), 7.56 (s, 1), 7.69 (d, 2), 8.10 (s, 1), 8.20 (s, 1)8.88 (d, 1) ppm.

D. Alternatively,2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-hydroxyquinoline(100 mg, 1.0 eq) and cesium carbonate (190 mg, 3.0 eq.) were combined in5 mL of DMF, and methyl α-bromophenylacetate (66 mg, 1.5 e q) was added.The resulting reaction mixture was stirred at 50° C. for 1 hour. Thenthe mixture was poured into 50 mL ice-water, extracted with 2×50 mlethyl acetate, and the organic phase was washed with 3×30 ml water, andthen brine. The crude product was purified by flash columnchromatography (acetate/gexane=1/1) to provide2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]-aminocarbonyl-4-(1-phenyl-1-methoxycarbonyl)methoxyquinoline(120 mg), which was dissolved in 2 mL of trifluoroacetic acid. Theresulting reaction mixture was stirred at ambient temperature for 20minutes, and then concentrated in vacuo. The residual oil was dissolvedin 30 mL ethyl acetate, washed with saturated NaHCO₃, brine, and driedin vacuo to afford (90 mg).2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(1-phenyl-1-methoxycarbonyl)methoxyquinoline(60 mg) in 3 mL MeOH was added to a solution of 15 mg (3 eq.) LiOH in 2mL water. The resulting reaction mixture was stirred at ambienttemperature for 2 hours. then the MeOH solvent was removed in vacuo. ThepH was adjusted to pH 3–4 with 2 N NaHSO₂, and extracted by 2×20 mLacetate to afford a white solid,2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(1-phenyl-1-carboxy)methoxyquinoline(40 mg).

E. In a similar manner, the following compounds of formula (Ib) wereprepared:

-   2-[1S-(4-(3-methylphenyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-benzyloxyquinoline;-   2-[1S-(4-(3-methylphenyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-benzyloxyquinoline;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-chloro-4-(1-carboxy-1-phenyl)methoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-naphth-1-yl-1-carboxy)methoxyquinoline;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-6-fluoro-4-(1-carboxy-1-(2-fluoro)phenyl)methoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-4-(1-ethoxycarbonyl-1-phenyl)methoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(5-methylisoxaxol-3-yl)methoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(2-methylthiazol-4-yl)methoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-methoxycarbonylpropyl]aminocarbonyl-4-(1-phenyl-1-ethoxycarbonyl-1-chloro)methoxyquinoline;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6,8-difluoro-4-(1-carboxy-1-phenyl)methoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-chloro-6-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline    in trifluoroacetic acid;-   2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-6-fluoro-4-(1-carboxy-1-thien-3-yl)methoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-chloro-7-methyl-4-(5-methylisoxazol-3-yl)methoxyquinoline;-   2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-chloro-7-methyl-4-(2-methylthiazol-4-yl)methoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-6-fluoro-4-(1-carboxy-1-(4-chloro)phenyl)methoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-6-fluoro-4-(1-carboxy-1-(3-methoxy)phenyl)methoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-dimethylamino-4-(1-phenyl-1-carboxy)methoxyquinoline;-   2-[1S-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline;-   2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline;-   2-[1S-(4-(3-methylphenyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline;-   2-[1S-(4-(3-methylphenyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)carbonyl-3-methoxycarbonylpropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline;-   2-[1S-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline;-   2-[1S-(4-(furan-2-ylcarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(methoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(1,1-dimethylethylaminocarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(phenyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline;    and-   2-[1S-(4-(phenyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline    in trifluoroacetic acid.

E. Alternatively,2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-hydroxyquinoline(100 mg, 1.0 eq) and cesium carbonate (300 mg, 2.5 eq) were combined in10 mL of DMF. Methyl 4-(bromomethyl)benzoate (65 mg, 1.1 eq) was addedto the solution and the resulting mixture was stirred at 50° C. for 30minutes. The reaction mixture was poured into 200 mL of ice water,extracted with 2×100 mL ethyl acetate, and the organic phase was washedwith 3×100 mL water, followed by a brine wash. The crude mixture waspurified by flash column chromatography to provide2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-(4-methoxycarbonyl)benzyloxyquinoline(107 mg). To a solution of2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-(4-methoxycarbonyl)benzyloxyquinoline(78 mg) in 4 mL THF was added a solution of 16 mg LiOH in 3 mL of water.The resulting reaction mixture was stirred at ambient temperature for 2hours, followed by standard work-up to provided 65 mg of2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-(4-carboxy)benzyloxyquinoline.

F. In a similar manner, the following compounds of formula (Ib) wereprepared:

-   2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-(3-methoxycarbonyl)benzyloxyquinoline;    and-   2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-(3-carboxy)benzyloxyquinoline.

G. Alternatively, to a suspension of NaH (53.0 mg, 2.20 mmol), DMF (8mL) was added a solution of2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-6-chloro-8-fluoro-4-hydroxyquinoline(500 mg, 0.88 mmol) in DMF (2 mL). The reaction mixture was stirred atambient temperature for 30 minutes. A solution of methylα-bromophenylacetate (4 eq., 831 mg ) in DMF (3 mL) was added dropwiseand the reaction mixture was heated at 50° C. overnight. The solvent,DMF, was evaporated in vacuo. The residue was treated with ethylacetate, washed with water (2×) and brine, followed by evaporation andflash column chromatography with 1–2% MeOH in DCM to afford2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-6-chloro-8-fluoro-4-(1-methoxycarbonyl-1-phenyl)methoxyquinoline(324 mg ).2-[1S-(4-(Ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-6-chloro-8-fluoro-4-(1-methoxycarbonyl-1-phenyl)methoxyquinoline(324 mg, 0.45 mmol) was then treated with TFA: DCM (1:1, 1.8 mL) atambient temperature for 4 hours. Evaporation, dilution with DCM, andrepeated evaporation gave a crude product. Flash column chromatographywith 100% ethyl acetate and 3–5% MeOH (with 0.1% acetic acid) in ethylacetate afforded2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-chloro-8-fluoro-4-(1-methoxycarbonyl-1-phenyl)methoxyquinolinein acetic acid; (233 mg ): NMR (CD₃OD) 1.25 (t, 3), 1.99 (m, 1), 2.2 (m,1), 2.45 (m, 2), 3.4–3.8 (m, 11), 4.16 (q, 2), 5.25 (m, 1), 6.38 (s, 1),7.45 (m, 3), 7.68 (m, 4), 8.10 (s, 1), 9.05 (m, 1) ppm.

H.2-[1S-(4-(Ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-chloro-8-fluoro-4-(1-methoxycarbonyl-1-phenyl)methoxyquinoline(154 mg, 0.233 mmol ) was added to a mixture of THF:H₂O, 3:1, 6.0 mL)and LiOH (4 eq.). The mixtutre was stirred at ambient temperature for1.5 hours. The pH value was adjusted to 3.0 with 1N HCl solution,followed by extraction with ethyl acetate and evaporation of solvent togive a crude product. Flash column chromatography with 100% ethylacetate and 5–10% MeOH (with 0.1% AcOH) in ethyl acetate afforded2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-chloro-8-fluoro-4-(1-carboxy-1-phenyl)methoxyquinolinein acetic acid (30 mg): NMR (CD₃OD) 1.25 (t, 3), 1.99 (m, 1), 2.2 (m,1), 2.45 (m, 2), 3.4–3.9 (m, 8), 4.16 (q, 2), 5.20 (m, 1), 6.35 (s, 1),7.45–7.75 (m, 7), 8.05 (s, 1), 9.02 (m, 1) ppm.

EXAMPLE 3 Compounds of Formulae (Ic), (Id) and (Ie)

A. To a mixture of2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-7-methyl-4-chloroquinoline(475 mg, 0.87 mmol) and CsCO₃ (1.13 g, 4 mmol) in 20 mL DMSO was addedmethyl 3-hydroxybenzoate (160 mg, 1 mmol). The reaction was heated at60° C. overnight. The reaction was filtered and purified by preparativeHPLC to afford2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-7-methyl-4-(3-methoxycarbonyl)-phenoxyquinoline(200 mg, 35%).

B.2-[1S-(4-(Ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-7-methyl-4-(3-methoxycarbonyl)phenoxyquinoline(200 mg, 0.3 mmol) was dissolved in a mixture of methylene chloride andtrifluoroacetic acid (5 mL, 4:1 mixture) and stirred for 3 hours. Thesolution was evaporated to an oil and dissolved in MeOH (10 mL). Lithiumhydroxide (3 mL, 0.25 M) was added and the solution was stirredovernight. The reaction was evaporated, adjusted to pH <7 with TFA andpurified by preparative HPLC to afford2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-4-(3-carboxy)phenoxyquinolinein trifluoroacetic acid, (25 mg, 15%). 1H NMR: (DMSO-d₆) 1.15 (t, 3),1.80 (m, 1), 2.00 (m, 1), 2.55 (s, 3), 3.30–3.60 (m, 8), 4.05 (q, ),4.95 (m, 1), 7.05 (s, 1), 7.61 (m, 2), 7.65 (d, 1), 7.75 (s, 1), 8.25(d. 1), 8.91 (d, 2) ppm.

C. In a similar manner, the following compounds of formula (Ic) wereprepared:

-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-carboxy)phenoxyquinoline    in 2,2,2-trifluoro-1,1-ethanediol;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(2-carboxy)phenoxyquinoline    in 2,2,2-trifluoro-1,1-ethanediol;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(2-amino-5-carboxy)phenoxyquinoline    in 2,2,2-trifluoro-1,1-ethanediol;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(4-carboxy)phenoxyquinoline    in 2,2,2-trifluoro-1,1-ethanediol;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-carboxymethyl)phenoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-(1-amino-1-carboxy)methyl)phenoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-(2-amino-2-carboxy)ethyl)phenoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(2-methyl-5-carboxy)phenoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(5-carboxy-2-diethylaminomethyl)phenoxyquinoline    in trifluoroacetic acid;-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-tetrazol-5-yl)phenoxyquinoline    in 2,2,2-trifluoro-1,1-ethanediol; and-   2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-trifluoromethylsulfonylamino)phenoxyquinoline    in trifluoroacetic acid.

D. A solution of2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(methoxycarbonyl)propyl]aminocarbonyl-4-chloroquinoline(0.15 g, 0.313 mmol) and 1,2,3,4-tetrahydroisoquinoline (0.15 mmol) wasmixed in 3 mL of DMSO and heated to 100° C. for 18 hours. The reactionwas purified by reversed-phase HPLC. The product was dissolved in 0.25 MLiOH solution and stirred for 6 hours. Purification by reversed-phaseHPLC afforded.2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)quinolinein trifluoroacetic acid, to form a compound of formula (Id).

E. In a similar manner, other compounds of formula (Id) were prepared.

F. A solution of2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-7-methyl-4-bromoquinoline(10 mg, 0.17 mmol), 3-carboxyphenylboronic acid (0.26 mmol), Pd(PPh₃)(40 mg), and 2 M sodium carbonate (217 μL) was combined in 10 mL oftoluene-ethanol and heated at 80° C. overnight. The reaction waspurified by reversed-phase HPLC. The product was dissolved in 10 mL of1/1 TFA-methylene chloride solution and stirred for 2 hours. The productwas concentrated in vacuo to afford2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-carboxy)phenylquinolinein trifluoroacetic acid.

G. In a similar manner, other compounds of formula (Ie) were prepared.

EXAMPLE 4 Receptor Binding Studies

The ability of the compounds of the invention to bind to the plateletadenosine diphosphate (“ADP”) receptor was tested using human washedplatelets and rat washed platelets by displacement assays.

Methods:

One day old platelet concentrates were purchased from a local bloodbank. The platelet concentrates were spun at 680 g for 10 minutes andthe resulting pellets were resuspended in modified Tyrode's buffer (135mM NaCl, 3.6 mL KCl, 1.8 mM MgCl₂, 9 mM HEPES, 0.18 mg/mL BSA, 4.5 mMglucose, pH 6.6) supplemented by 2% acid citrate dextrose (ACD). Thisplatelet suspension was spun at 680 g for 10 minutes and the finalpellet was resuspended in platelet binding buffer (20 mM Tris buffer, pH7.5, 140 mM NaCl, 4 mM KCl, 2 mM MgCl₂, 1 mM EDTA, 0.1% BSA, 5 mMglucose, 2 μg/mL aprotinin, and 2 μg/mL leupeptin).

Platelets were isolated from rat whole blood as described in Example 13with the final pellet resuspended in platelet binding buffer. Theplatelet number for binding to rat platelets (5×10⁶ per well) wasnormalized to the number of platelets for binding to human platelet(4–6×10⁶ per well).

Binding reactions were initiated by mixing [³³P]-2-methylthio-ADP(0.3–0.5 nM), test compounds and washed platelets in 96-well plates. Thereactions were kept at ambient temperature for 60 minutes under constantshaking and were stopped by fast-filtration onto 96-well, glass-fiber(GFC) filter plates followed by washing 5 times with ice-cold 50 mM Trisbuffer (pH 7.5). The amount of [³³P]-2-methylthio-ADP bound to thefilters was measured by scintillation counting. Non-specific binding wasdetermined in the presence of 10 μM unlabelled 2-methylthio-ADP.Competition studies were done using a single concentration of[³³P]-2-methylthio-ADP (0.3 nM) and varying concentrations of testcompounds.

Results:

The compounds of the invention, when tested in this assay, demonstratedtheir ability to inhibitor the binding of [³³P]-2-methylthio-ADP bindingto the human platelet ADP receptor and the rat platelet ADP receptor.

EXAMPLE 5 ADP-Induced Aggregation In Vitro Studies

The compounds of the invention were evaluated as functional antagonistsof the platelet ADP receptor using both human and rat washed platelets.

Methods:

Human venous blood was collected from healthy, drug-free volunteers into⅙ volume 3.2% acid/citrate/dextrose. Whole blood fromNembutal-anesthetized rats was collected from the abdominal aorta into1/10 volume 3.8% acid/citrate/dextrose. Platelet rich plasma (PRP) wasprepared by centrifugation at 800 g for 3–4 successive 1.5-minuteintervals, with removal of the PRP after each spin. Alternatively, somePRP preps were performed by centrifugation at 100 g for 15 minutes.Washed platelets were prepared from the PRP by centrifugation at 680 gfor 15 minutes and the platelet pellet resuspended in Tyrode's buffer(137 mM NaCl, 2.7 mM KCl, 12 mM NaHCO₂, 0.42 mM NaH₂PO, 1 mM MgCl₂, 2 mMCaCl₂, 0.35% BSA, 5.5 mM glucose, 5 mM HEPES, pH 7.35 supplemented withf.c. 10% ACD solution. The platelets were washed a total of two timesunder these acidic conditions and the platelet pellet collected bycentrifugation at 680 g for 15 minutes at ambient temperature. The finalplatelet pellet was resuspended at 2×10⁸ platelets/mL in Tyrode's buffercontaining 0.02 units/mL apyrase. This platelet suspension was kept at37° C. for at least 30 minutes prior to studies.

Inhibition of ADP-induced aggregation was measured at 37° C. in a4-channel aggregometer. The platelet suspension (0.5 mL) was stirred at1200 rpm. Human fibrinogen (400 μg) was added at time zero for 1 minutefollowed by 2 minute pre-incubation in the presence or absence ofantagonist. Platelet aggregation was induced with the addition of 10 or31.6 μM ADP (submaximal response) in human platelets or 3 or 10 μM ADP(submaximal response) in rat and monitored for 5 minutes. ADP-inducedaggregation was quantified by measuring increase in light transmission(% T) compared to Tyrode's buffer control. IC₅₀ values were determinedusing the 4-parameter equation.

Results:

The compounds of the invention, when tested in this assay, demonstratedthe ability to inhibit ADP-induced platelet aggregation in vitro inhuman and rat washed platelets.

EXAMPLE 6 Efficacy Assay

Inhibition of thrombus formation by compounds of the invention wasevaluated in the rat arterio-venous (A-V) shunt model.

Methods:

Male Sprague-Dawley rats (350–400 g, 10–18 per group) were anesthetizedwith Nembutal (65 mg/kg, i.p). The left carotid artery and the rightjugular vein were each cannulated with a piece of PE-50 tubing (8 cm,siliconized). Fifty minutes after anesthesia, the arterial and venouscatheters were connected (A-V shunt) by a piece of shunt tubing (TygonS-50-HL, 6 cm) that contained a silk thread (6-0 silk suture, 10 cm)coated with collagen (Horm, 100 μg/ml). Blood was allowed to flowthrough the A-V shunt for 10 minutes. The amount of thrombus depositedon the silk thread was measured as dry weight (24 hours at ambienttemperature). A compound of the invention (1, 3 and 10 mg/kg) (as theappropriate salt form) or vehicle (15% DMSO in saline, 1 mL/kg) wasinjected via the jugular vein catheter 5 minutes before the A-V shunt.Blood samples (1 mL) were taken immediately before the dosing and at theend of the A-V shunt for measurements of ex vivo platelet aggregationand plasma levels of the compound of the invention.

Results:

When tested in this assay, compounds of the invention demonstrated theability to dose-dependently inhibit platelet aggregation and thrombusformation in the rat A-V shunt model. Both the inhibition of plateletaggregation and thrombus formation were also parallel in relation to thechanges in plasma drug concentrations. Thus, the inhibition of thrombusformation is correlated with the inhibition of platelet aggregationinduced by the compound of the invention.

EXAMPLE 7

This example illustrates the preparation of representativepharmaceutical compositions for oral administration containing acompound of the invention, or a pharmaceutically acceptable saltthereof:

A. Ingredients % wt./wt. Compound of the invention 20.0% Lactose 79.5%Magnesium stearate 0.5%

The above ingredients are mixed and dispensed into hard-shell gelatincapsules containing 100 mg each, one capsule would approximate a totaldaily dosage.

B. Ingredients % wt./wt. Compound of the invention 20.0% Magnesiumstearate 0.9% Starch 8.6% Lactose 69.6% PVP (polyvinylpyrrolidine) 0.9%

The above ingredients with the exception of the magnesium stearate arecombined and granulated using water as a granulating liquid. Theformulation is then dried, mixed with the magnesium stearate and formedinto tablets with an appropriate tableting machine.

C. Ingredients Compound of the invention  0.1 g Propylene glycol 20.0 gPolyethylene glycol 400 20.0 g Polysorbate 80  1.0 g Water q.s. 100 mL

The compound of the invention is dissolved in propylene glycol,polyethylene glycol 400 and polysorbate 80. A sufficient quantity ofwater is then added with stirring to provide 100 mL of the solutionwhich is filtered and bottled.

D. Ingredients % wt./wt. Compound of the invention 20.0% Peanut Oil78.0% Span 60 2.0%

The above ingredients are melted, mixed and filled into soft elasticcapsules.

E. Ingredients % wt./wt. Compound of the invention 1.0% Methyl orcarboxymethyl cellulose 2.0% 0.9% saline q.s. 100 mL

The compound of the invention is dissolved in the cellulose/salinesolution, filtered and bottled for use.

EXAMPLE 8

This example illustrates the preparation of a representativepharmaceutical formulation for parenteral administration containing acompound of the invention, or a pharmaceutically acceptable saltthereof:

Ingredients Compound of the invention 0.02 g Propylene glycol 20.0 gPolyethylene glycol 400 20.0 g Polysorbate 80 1.0 g 0.9% Saline solutionq.s. 100 mL

The compound of the invention is dissolved in propylene glycol,polyethylene glycol 400 and polysorbate 80. A sufficient quantity of0.9% saline solution is then added with stirring to provide 100 mL ofthe I.V. solution which is filtered through a 0.2 m membrane filter andpackaged under sterile conditions.

EXAMPLE 9

This example illustrates the preparation of a representativepharmaceutical composition in suppository form containing a compound ofthe invention, or a pharmaceutically acceptable salt thereof:

Ingredients % wt./wt. Compound of the invention 1.0% Polyethylene glycol1000 74.5% Polyethylene glycol 4000 24.5%

The ingredients are melted together and mixed on a steam bath, andpoured into molds containing 2.5 g total weight.

EXAMPLE 10

This example illustrates the preparation of a representativepharmaceutical formulation for insufflation containing a compound of theinvention, or a pharmaceutically acceptable salt thereof:

Ingredients % wt./wt. Micronized compound of the invention 1.0%Micronized lactose 99.0%

The ingredients are milled, mixed, and packaged in an insufflatorequipped with a dosing pump.

EXAMPLE 11

This example illustrates the preparation of a representativepharmaceutical formulation in nebulized form containing a compound ofthe invention, or a pharmaceutically acceptable salt thereof:

Ingredients % wt./wt. Compound of the invention 0.005% Water 89.995%Ethanol 10.000%

The compound of the invention is dissolved in ethanol and blended withwater. The formulation is then packaged in a nebulizer equipped with adosing pump.

EXAMPLE 12

This example illustrates the preparation of a representativepharmaceutical formulation in aerosol form containing a compound of theinvention, or a pharmaceutically acceptable salt thereof:

Ingredients % wt./wt. Compound of the invention 0.10% Propellant 11/1298.90% Oleic acid 1.00%

The compound of the invention is dispersed in oleic acid and thepropellants. The resulting mixture is then poured into an aerosolcontainer fitted with a metering valve.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

1. A compound of formula (I):

wherein: m and n are independently 1 to 4; R¹ is hydrogen, alkyl,carboxyalkyl, aryl, aralkyl, alkylcarbonyl, aryloxyalkylcarbonyl,carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylalkyl,alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl,cycloalkylcarbonyl, haloalkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, dialkylaminocarbonyl,alkoxycarbonylaminocarbonyl, or heterocyclylcarbonyl; R² is hydrogen,alkyl, aryl, aralkyl, alkylsulfonylalkyl, aralkoxyalkyl, hydroxyalkyl,aminoalkyl, haloalkylsulfonylaminoalkyl, carboxyalkylthioalkyl,alkoxycarbonylalkylthioalkyl, carboxyalkyl, (carboxy)(hydroxy)alkyl,carboxyalkoxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl,carboxyalkoxycarbonylalkyl, alkoxycarbonylalkoxycarbonylalkyl,aminocarbonylalkyl, aralkoxycarbonylaminoalkyl,alkoxycarbonylalkylaminocarbonylalkyl, carboxyalkylaminocarbonylalkyl,(alkoxycarbonylalkyl)(alkyl)aminocarbonylalkyl,(carboxyalkyl)(alkyl)aminocarbonylalkyl, or heterocyclylalkyl; R³ isaryl or aryloxy each independently optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo,haloalkyl, cyano, nitro, tetrazolyl, —R⁸—OR⁷, —R⁸—C(O)OR⁷,—R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷, —R⁸—N(R⁷)₂, —R⁸—N(R⁷)C(O)R⁷,—R⁸—N(R⁷)C(O)OR⁹, —R⁸—N(R⁷)—S(O)₂—R⁷, and —R⁸—C[N(R⁷)₂]—C(O)OR⁷; or R³is aralkyl or aralkoxy, wherein the alkyl radical in the aralkyl oraralkoxy substituent is optionally substituted by one or moresubstituents selected from the group consisting of halo, cyano, nitro,—R⁸—OR⁷, —R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷, —R⁸—N(R⁷)₂,—R⁸—N(R⁷)C(O)R⁷, and —R⁹—N(R⁷)C(O)OR⁹), and wherein the aryl radical inthe aralkyl or aralkoxy substituent is independently optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, —R⁸—OR⁷,—R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷, —R⁸—N(R⁷)₂, —R⁸—N(R⁷)C(O)R⁷,—R⁸—N(R⁷)C(O)OR⁹, —R⁸—N(R⁷)—S(O)₂—R⁷, and —R⁸—C[N(R⁷)₂]—C(O)OR⁷; each R⁴is independently selected from the group consisting of hydrogen, alkyl,alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano,alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyl, nitro,amino, monoalkylamino, dialkylamino, carboxyalkylamino,alkylcarbonylamino, di(alkylcarbonyl)amino, hydroxyalkyl,dialkylaminoalkyl, carboxyalkoxy, alkoxycarbonylalkoxy,dialkylaminoalkoxy, and heterocyclylalkoxy; each R⁵ is independentlyselected from the group consisting of hydrogen, alkyl, hydroxyalkyl,aralkyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl, carboxyalkyl, andalkoxycarbonylalkyl; R⁶ is hydrogen, alkyl, carboxyalkyl, oralkoxycarbonylalkyl; each R⁷ is hydrogen, alkyl, aryl, aralkyl, orhaloalkyl; each R⁸ is a bond or a straight or branched alkylene chain;and each R⁹ is hydrogen, alkyl, aralkyl or haloalkyl; as a singlestereoisomer, a mixture of individual stereoisomers, or a racemicmixture; or a pharmaceutically acceptable salt thereof.
 2. The compoundof claim 1 wherein: m is 1; n is 1 or 2; R¹ is hydrogen, aryl, aralkyl,or alkoxycarbonyl; R² is hydrogen, carboxyalkyl, alkoxycarbonylalkyl oraralkoxycarbonylalkyl; R³ is aryl optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo,haloalkyl, cyano, nitro, —R⁸—OR⁷, —R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂,—R⁸—C(O)R⁷, —R⁸—N(R⁷)₂, —R⁸—N(R⁷)C(O)R⁷, and —R⁸—N(R⁷)C(O)OR⁹; each R⁴is is independently selected from the group consisting of hydrogen,alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano,alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyl, nitro,amino, monoalkylamino, dialkylamino, carboxyalkylamino,alkylcarbonylamino, di(alkylcarbonyl)amino, hydroxyalkyl,dialkylaminoalkyl, carboxyalkoxy, alkoxycarbonylalkoxy,dialkylaminoalkoxy, and heterocyclylalkoxy; R⁵ is hydrogen; R⁶ ishydrogen or alkyl; each R⁷ is hydrogen, alkyl, aryl, aralkyl, orhaloalkyl; each R⁸ is a bond or a straight or branched alkylene chain;and R⁹ is hydrogen, alkyl, aralkyl or haloalkyl.
 3. The compound ofclaim 2 wherein: m is 1; n is 1 or 2; R¹ is hydrogen or alkoxycarbonyl;R² is hydrogen, carboxyalkyl, alkoxycarbonylalkyl oraralkoxycarbonylalkyl; R³ is aryl optionally substituted by one or moresubstituents selected from the group consisting of carboxy oralkoxycarbonyl; each R⁴ is is independently selected from the groupconsisting of hydrogen, alkyl, halo, or haloalkyl; R⁵ is hydrogen; andR⁶ is hydrogen.
 4. The compound2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-carboxy),according to claim
 3. 5. The compound of claim 1 wherein: m is 1; n is 1or 2; R¹ is hydrogen, aryl, aralkyl, or alkoxycarbonyl; R² is hydrogen,carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl; R³ isaryloxy optionally substituted by one or more substituents selected fromthe group consisting of alkyl, halo, haloalkyl, cyano, nitro,tetrazolyl, —R⁸—OR⁷, —R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷,—R⁸—N(R⁷)₂, —R⁸—N(R⁷)C(O)R⁷, —R⁸—N(R⁷)C(O)OR⁹, —R⁸—N(R⁷)—S(O)₂—R⁷, and—R⁸—C[N(R⁷)₂]—C(O)OR⁷; each R⁴ is independently selected from the groupconsisting of hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl,haloalkoxy, hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl,aminocarbonyl, alkylcarbonyl, nitro, amino, monoalkylamino,dialkylamino, carboxyalkylamino, alkylcarbonylamino,di(alkylcarbonyl)amino, hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy,alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclylalkoxy; R⁵ isselected from the group consisting of hydrogen, alkyl, hydroxyalkyl,aralkyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl, carboxyalkyl, andalkoxycarbonylalkyl; R⁶ is hydrogen, alkyl, carboxyalkyl, oralkoxycarbonylalkyl; each R⁷ is hydrogen, alkyl, aryl, aralkyl, orhaloalkyl; each R⁸ is a bond or a straight or branched alkylene chain;and R⁹ is hydrogen, alkyl, aralkyl or haloalkyl.
 6. The compound ofclaim 5 wherein: m is 1; n is 1 or 2; R¹ is hydrogen or alkoxycarbonyl;R² is hydrogen, carboxyalkyl, alkoxycarbonylalkyl oraralkoxycarbonylalkyl; R³ is aryloxy optionally substituted by one ormore substituents selected from the group consisting of alkyl,tetrazolyl, —R⁸—C(O)OR⁷, —R⁸—N(R⁷)₂, —R⁸—N(R⁷)—S(O)₂—R⁷, and—R⁸—C[N(R⁷)₂]—C(O)OR⁷; each R⁴ is is independently selected from thegroup consisting of hydrogen, alkyl, halo, or haloalkyl; R⁵ is hydrogen;R⁶ is hydrogen; each R⁷ is hydrogen, alkyl, aryl, aralkyl, or haloalkyl;and each R⁸ is a bond or a straight or branched alkylene chain.
 7. Thecompound of claim 6 selected from the group consisting of the following:2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-carboxy)phenoxyquinoline;2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(2-carboxy)phenoxyquinoline;2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(2-amino-5-carboxy)phenoxyquinoline;2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(4-carboxy)phenoxyquinoline;2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-carboxymethyl)phenoxyquinoline;2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-(1-amino-1-carboxy)methyl)phenoxyquinoline;2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-(2-amino-2-carboxy)ethyl)phenoxyquinoline;2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(2-methyl-5-carboxy)phenoxyquinoline;2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(5-carboxy-2-diethylaminomethyl)phenoxyquinoline;2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-tetrazol-5-yl)phenoxyquinoline;2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-trifluoromethylsulfonylamino)phenoxyquinoline;and2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-4-(3-carboxy)phenoxyquinoline.8. The compound of claim 1 wherein m is 1; n is 1 or 2; R¹ is hydrogen,aryl, aralkyl, or alkoxycarbonyl; R² is hydrogen, carboxyalkyl,alkoxycarbonylalkyl or aralkoxycarbonylalkyl; R³ is aralkyl wherein thealkyl radical in the aralkyl substituent is optionally substituted byone or more substituents selected from the group consisting of halo,cyano, nitro, —R⁸—OR⁷, —R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷,—R⁸—N(R⁷)₂, —R⁸—N(R⁷)C(O)R⁷, and —R⁹—N(R⁷)C(O)OR⁹), and wherein the arylradical in the aralkyl substituent is independently optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, —R⁸—OR⁷,—R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷, —R⁸—N(R⁷)₂, —R⁸—N(R⁷)C(O)R⁷,—R⁸—N(R⁷)C(O)OR⁹, —R⁸—N(R⁷)—S(O)₂—R⁷, and —R⁸—C[N(R⁷)₂]—C(O)OR⁷; each R⁴is independently selected from the group consisting of hydrogen, alkyl,alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano,alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyl, nitro,amino, monoalkylamino, dialkylamino, carboxyalkylamino,alkylcarbonylamino, di(alkylcarbonyl)amino, hydroxyalkyl,dialkylaminoalkyl, carboxyalkoxy, alkoxycarbonylalkoxy,dialkylaminoalkoxy, and heterocyclylalkoxy; R⁵ is selected from thegroup consisting of hydrogen, alkyl, hydroxyalkyl, aralkyl, carboxy,alkoxycarbonyl, aralkoxycarbonyl, carboxyalkyl, and alkoxycarbonylalkyl;R⁶ is hydrogen, alkyl, carboxyalkyl, or alkoxycarbonylalkyl; each R⁷ ishydrogen, alkyl, aryl, aralkyl, or haloalkyl; each R⁸ is a bond or astraight or branched alkylene chain; and R⁹ is hydrogen, alkyl, aralkylor haloalkyl.
 9. The compound of claim 1 wherein: m is 1; n is 1 or 2;R¹ is hydrogen, aryl, aralkyl, or alkoxycarbonyl; R² is hydrogen,carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl; R³ isaralkoxy wherein the alkyl radical in the aralkyl substituent is notoptionally substituted and wherein the aryl radical in the aralkoxysubstituent is optionally substituted by one or more substituentsselected from the group consisting of alkyl, halo, haloalkyl, cyano,nitro, tetrazolyl, —R⁸—OR⁷, —R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷,—R⁸—N(R⁷)₂, —R⁸—N(R⁷)C(O)R⁷, —R⁸—N(R⁷)C(O)OR⁹, —R⁸—N(R⁷)—S(O)₂—R⁷, and—R⁸—C[N(R⁷)₂]—C(O)OR⁷; each R⁴ is independently selected from the groupconsisting of hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl,haloalkoxy, hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl,aminocarbonyl, alkylcarbonyl, nitro, amino, monoalkylamino,dialkylamino, carboxyalkylamino, alkylcarbonylamino,di(alkylcarbonyl)amino, hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy,alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclylalkoxy; R⁵ isselected from the group consisting of hydrogen, alkyl, hydroxyalkyl,aralkyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl, carboxyalkyl, andalkoxycarbonylalkyl; R⁶ is hydrogen, alkyl, carboxyalkyl, oralkoxycarbonylalkyl; each R⁷ is hydrogen, alkyl, aryl, aralkyl, orhaloalkyl; each R⁸ is a bond or a straight or branched alkylene chain;and R⁹ is hydrogen, alkyl, aralkyl or haloalkyl.
 10. The compound ofclaim 9 wherein: m is 1; n is 1 or 2; R¹ is hydrogen, aryl, aralkyl, oralkoxycarbonyl; R² is hydrogen, carboxyalkyl, alkoxycarbonylalkyl oraralkoxycarbonylalkyl; R³ is aralkoxy wherein the aryl radical in thearalkoxy substituent is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo,haloalkyl, —R⁸—OR⁷—R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂, and —R⁸—N(R⁷)₂; each R⁴is independently selected from the group consisting of hydrogen, alkyl,alkoxy, halo, or haloalkyl; R⁵ is hydrogen; R⁶ is hydrogen; each R⁷ ishydrogen, alkyl, aryl, aralkyl, or haloalkyl; and each R⁸ is a bond or astraight or branched alkylene chain.
 11. The compound selected from thegroup consisting of the following:2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-benzyloxyquinoline;2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-benzyloxycarbonylpropyl]aminocarbonyl-4-benzyloxyquinoline;2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-benzyloxyquinoline;2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-benzyloxycarbonylpropyl]aminocarbonyl-4-benzyloxy-8-methoxyquinoline;2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-benzyloxy-8-methoxyquinoline;2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-(4-methoxycarbonyl)benzyloxyquinoline;2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-(4-carboxy)benzyloxyquinoline;2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-(3-methoxycarbonyl)benzyloxyquinoline;2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-(3-carboxy)benzyloxyquinoline;2-[1S-(4-(3-methylphenyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-benzyloxyquinoline;and2-[1S-(4-(3-methylphenyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-benzyloxyquinoline.12. The compound of claim 1 wherein: m is 1; n is 1 or 2; R¹ ishydrogen, aryl, aralkyl, or alkoxycarbonyl; R² is hydrogen,carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl; R³ isaralkoxy wherein the alkyl radical in the aralkoxy substituent issubstituted by one or more substituents selected from the groupconsisting of halo, cyano, nitro, —R⁸—OR⁷, —R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂,—R⁸—C(O)R⁷, —R⁸—N(R⁷)₂, —R⁸—N(R⁷)C(O)R⁷, and —R⁹—N(R⁷)C(O)OR⁹), andwherein the aryl radical in the aralkoxy substituent is optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, —R⁸—OR⁷,—R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷, —R⁸—N(R⁷)₂, —R⁸—N(R⁷)C(O)R⁷,—R⁸—N(R⁷)C(O)OR⁹, —R⁸—N(R⁷)—S(O)₂—R⁷, and —R⁸—C[N(R⁷)₂]—C(O)OR⁷; each R⁴is independently selected from the group consisting of hydrogen, alkyl,alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano,alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyl, nitro,amino, monoalkylamino, dialkylamino, carboxyalkylamino,alkylcarbonylamino, di(alkylcarbonyl)amino, hydroxyalkyl,dialkylaminoalkyl, carboxyalkoxy, alkoxycarbonylalkoxy,dialkylaminoalkoxy, and heterocyclylalkoxy; R⁵ is selected from thegroup consisting of hydrogen, alkyl, hydroxyalkyl, aralkyl, carboxy,alkoxycarbonyl, aralkoxycarbonyl, carboxyalkyl, and alkoxycarbonylalkyl;R⁶ is hydrogen, alkyl, carboxyalkyl, or alkoxycarbonylalkyl; each R⁷ ishydrogen, alkyl, aryl, aralkyl, or haloalkyl; each R⁸ is a bond or astraight or branched alkylene chain; and R⁹ is hydrogen, alkyl, aralkylor haloalkyl.
 13. The compound of claim 12 wherein: m is 1; n is 1 or 2;R¹ is hydrogen, aryl, aralkyl, or alkoxycarbonyl; R² is hydrogen,carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl; R³ isaralkoxy wherein the alkyl radical in the aralkoxy substituent issubstituted by —R⁸—C(O)OR⁷, and wherein the aryl radical in the aralkoxysubstituent is optionally substituted by one or more substituentsselected from the group consisting of halo and —R⁸—OR⁷; each R⁴ isindependently selected from the group consisting of hydrogen, alkyl,alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino; R⁵ ishydrogen; R⁶ is hydrogen; each R⁷ is hydrogen, alkyl, aryl, aralkyl, orhaloalkyl; and each R⁸ is a bond or a straight or branched alkylenechain.
 14. The compound of claim 13 selected from the group consistingof the following:2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-(1-phenyl-1-methoxycarbonyl)methoxyquinoline;2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(1-phenyl-1-methoxycarbonyl)methoxyquinoline;2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(1-phenyl-1-carboxy)methoxyquinoline;2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline;2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline;2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-chloro-4-(1-carboxy-1-phenyl)methoxyquinoline;2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-naphth-1-yl-1-carboxy)methoxyquinoline;2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-chloro-8-fluoro-4-(1-methoxycarbonyl-1-phenyl)methoxyquinoline;2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-chloro-8-fluoro-4-(1-carboxy-1-phenyl)methoxyquinoline;2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-6-fluoro-4-(1-carboxy-1-(2-fluoro)phenyl)methoxyquinolinein trifluoroacetic acid;2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-4-(1-ethoxycarbonyl-1-phenyl)methoxyquinoline;2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline;2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-6-fluoro-4-(1-carboxy-1-(4-chloro)phenyl)methoxyquinoline;2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-6-fluoro-4-(1-carboxy-1-(3-methoxy)phenyl)methoxyquinoline;2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6,8-difluoro-4-(1-carboxy-1-phenyl)methoxyquinoline;2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-dimethylamino-4-(1-phenyl-1-carboxy)methoxyquinoline;2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-chloro-6-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline;2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-6-chloro-4-(1-phenyl-1-carboxy)methoxyquinoline;2-[1S-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)carbonyl-3-methoxycarbonylpropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline;2-[1S-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline;2-[1S-(4-(methoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline;2-[1S-(4-(1,1-dimethylethylaminocarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline;2-[1S-(4-(furan-2-ylcarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline;2-[1S-(4-(3-methylphenyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline;2-[1S-(4-(3-methylphenyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline;2-[1S-(4-(phenyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline;and2-[1S-(4-(phenyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline.15. A pharmaceutical composition useful in treating a mammal having adisease-state characterized by thrombotic activity, which compositioncomprises a pharmaceutically acceptable excipient and a compound offormula (I):

wherein: m and n are independently 1 to 4; R¹ is hydrogen, alkyl,carboxyalkyl, aryl, aralkyl, alkylcarbonyl, aryloxyalkylcarbonyl,carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylalkyl,alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl,cycloalkylcarbonyl, haloalkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, dialkylaminocarbonyl,alkoxycarbonylaminocarbonyl, or heterocyclylcarbonyl; R² is hydrogen,alkyl, aryl, aralkyl, alkylsulfonylalkyl, aralkoxyalkyl, hydroxyalkyl,aminoalkyl, haloalkylsulfonylaminoalkyl, carboxyalkylthioalkyl,alkoxycarbonylalkylthioalkyl, carboxyalkyl, (carboxy)(hydroxy)alkyl,carboxyalkoxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl,carboxyalkoxycarbonylalkyl, alkoxycarbonylalkoxycarbonylalkyl,aminocarbonylalkyl, aralkoxycarbonylaminoalkyl,alkoxycarbonylalkylaminocarbonylalkyl, carboxyalkylaminocarbonylalkyl,(alkoxycarbonylalkyl)(alkyl)aminocarbonylalkyl,(carboxyalkyl)(alkyl)aminocarbonylalkyl, or heterocyclylalkyl; R³ isaryl or aryloxy each independently optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo,haloalkyl, cyano, nitro, tetrazolyl, —R⁸—OR⁷, —R⁸—C(O)OR⁷,—R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷, —R⁸—N(R⁷)₂, —R⁸—N(R⁷)C(O)R⁷,—R⁸—N(R⁷)C(O)OR⁹, —R⁸—N(R⁷)—S(O)₂—R⁷, and —R⁸—C[N(R⁷)₂]—C(O)OR⁷; or R³is aralkyl or aralkoxy, wherein the alkyl radical in the aralkyl oraralkoxy substituent is optionally substituted by one or moresubstituents selected from the group consisting of halo, cyano, nitro,—R⁸—OR⁷, —R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷, —R⁸—N(R⁷)₂,—R⁸—N(R⁷)C(O)R⁷, and —R⁹—N(R⁷)C(O)OR⁹), and wherein the aryl radical inthe aralkyl or aralkoxy substituent is independently optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, —R⁸—OR⁷,—R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷, —R⁸—N(R⁷)₂, —R⁸—N(R⁷)C(O)R⁷,—R⁸—N(R⁷)C(O)OR⁹, —R⁸—N(R⁷)—S(O)₂—R⁷, and —R⁸—C[N(R⁷)₂]—C(O)OR⁷; each R⁴is independently selected from the group consisting of hydrogen, alkyl,alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano,alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyl, nitro,amino, monoalkylamino, dialkylamino, carboxyalkylamino,alkylcarbonylamino, di(alkylcarbonyl)amino, hydroxyalkyl,dialkylaminoalkyl, carboxyalkoxy, alkoxycarbonylalkoxy,dialkylaminoalkoxy, and heterocyclylalkoxy; each R⁵ is independentlyselected from the group consisting of hydrogen, alkyl, hydroxyalkyl,aralkyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl, carboxyalkyl, andalkoxycarbonylalkyl; R⁶ is hydrogen, alkyl, carboxyalkyl, oralkoxycarbonylalkyl; each R⁷ is hydrogen, alkyl, aryl, aralkyl, orhaloalkyl; each R⁸ is a bond or a straight or branched alkylene chain;and each R⁹ is hydrogen, alkyl, aralkyl or haloalkyl; as a singlestereoisomer, a mixture of individual stereoisomers, or a racemicmixture; or a pharmaceutically acceptable salt thereof.
 16. A method oftreating a disease-state characterized by thrombotic activity, whichmethod comprises administering to a mammal having a disease-statecharacterized by thrombotic activity a therapeutically effective amountof a compound of formula (I):

wherein: m and n are independently 1 to 4; R¹ is hydrogen, alkyl,carboxyalkyl, aryl, aralkyl, alkylcarbonyl, aryloxyalkylcarbonyl,carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylalkyl,alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl,cycloalkylcarbonyl, haloalkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, dialkylaminocarbonyl,alkoxycarbonylaminocarbonyl, or heterocyclylcarbonyl; R² is hydrogen,alkyl, aryl, aralkyl, alkylsulfonylalkyl, aralkoxyalkyl, hydroxyalkyl,aminoalkyl, haloalkylsulfonylaminoalkyl, carboxyalkylthioalkyl,alkoxycarbonylalkylthioalkyl, carboxyalkyl, (carboxy)(hydroxy)alkyl,carboxyalkoxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl,carboxyalkoxycarbonylalkyl, alkoxycarbonylalkoxycarbonylalkyl,aminocarbonylalkyl, aralkoxycarbonylaminoalkyl,alkoxycarbonylalkylaminocarbonylalkyl, carboxyalkylaminocarbonylalkyl,(alkoxycarbonylalkyl)(alkyl)aminocarbonylalkyl,(carboxyalkyl)(alkyl)aminocarbonylalkyl, or heterocyclylalkyl; R³ isaryl or aryloxy each independently optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo,haloalkyl, cyano, nitro, tetrazolyl, —R⁸—OR⁷, —R⁸—C(O)OR⁷,—R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷, —R⁸—N(R⁷)₂, —R⁸—N(R⁷)C(O)R⁷,—R⁸—N(R⁷)C(O)OR⁹, —R⁸—N(R⁷)—S(O)₂—R⁷, and —R⁸—C[N(R⁷)₂]—C(O)OR⁷; or R³is aralkyl or aralkoxy, wherein the alkyl radical in the aralkyl oraralkoxy substituent is optionally substituted by one or moresubstituents selected from the group consisting of halo, cyano, nitro,—R⁸—OR⁷, —R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷, —R⁸—N(R⁷)₂,—R⁸—N(R⁷)C(O)R⁷, and —R⁹—N(R⁷)C(O)OR⁹), and wherein the aryl radical inthe aralkyl or aralkoxy substituent is independently optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, —R⁸—OR⁷,—R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂, —R⁸—C(O)R⁷, —R⁸—N(R⁷)₂, —R⁸—N(R⁷)C(O)R⁷,—R⁸—N(R⁷)C(O)OR⁹, —R⁸—N(R⁷)—S(O)₂—R⁷, and —R⁸—C[N(R⁷)₂]—C(O)OR⁷; each R⁴is independently selected from the group consisting of hydrogen, alkyl,alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano,alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyl, nitro,amino, monoalkylamino, dialkylamino, carboxyalkylamino,alkylcarbonylamino, di(alkylcarbonyl)amino, hydroxyalkyl,dialkylaminoalkyl, carboxyalkoxy, alkoxycarbonylalkoxy,dialkylaminoalkoxy, and heterocyclylalkoxy; each R⁵ is independentlyselected from the group consisting of hydrogen, alkyl, hydroxyalkyl,aralkyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl, carboxyalkyl, andalkoxycarbonylalkyl; R⁶ is hydrogen, alkyl, carboxyalkyl, oralkoxycarbonylalkyl; each R⁷ is hydrogen, alkyl, aryl, aralkyl, orhaloalkyl; each R⁸ is a bond or a straight or branched alkylene chain;and each R⁹ is hydrogen, alkyl, aralkyl or haloalkyl; as a singlestereoisomer, a mixture of individual stereoisomers, or a racemicmixture; or a pharmaceutically acceptable salt thereof.